In the aftermath of their journey to another planet, Director Phil Coulson and the rest of the team were driven more than ever to put an end to the HYDRA organization. Little did they know that they were up against the deadliest threat they've ever faced – an extremely powerful Inhuman, Hive, who was transported back from Maveth in the body of their worst enemy, Grant Ward. The team was able to thwart and kill Hive and take down HYDRA, but they are all still mourning the death of fellow agent and Inhuman, Lincoln Campbell.
In light of the Sokovia Accords, and with HYDRA obliterated, S.H.I.E.L.D. has been legitimized again and no longer needs to operate in the shadows. Since the world presumes that Coulson is dead, the organization needed a new Director to be the face of the organization. Coulson finds himself back in the role as an agent and teamed with Mack, and together they are tasked with tracking down and confirming the presence of Enhanced people, aka Inhumans. They have been trying to track down and capture Daisy, aka Quake, who has gone rogue in an attempt to atone for sins from the past. But with the world believing that Daisy is a dangerous outlaw who has taken down banks and bridges, the new Director has no qualms about taking her down for good. Agent May is tasked with training specialist strike teams, and Fitz and Simmons have taken a big step forward in their relationship. But with Simmons' new promotion as Special Advisor to the Director in Science and Technology, Fitz, as well as her former team members, finds it hard to confide in or trust her since she's now the Director's confidant.
Robbie Reyes will roar into the lives of Agent Coulson and the team as a junkyard mechanic who can turn on a dime into the terrifying Ghost Rider. Will Robbie be a friend or foe to S.H.I.E.L.D. – as well as the world, itself? Meanwhile, Fitz discovers that socially awkward genius and friend Dr. Radcliffe has started putting the finishing touches on a new, secret invention.
On the heels of their encounter with Ghost Rider, their strangest phenomenon yet, the Agents of S.H.I.E.L.D. suddenly find themselves up against a myriad of new and ongoing threats: The anti-Inhuman Watchdogs are gaining political influence with Senator Nadeer, and uniting behind a mysterious benefactor. Meanwhile, unbeknownst to the team, Aida has kidnapped Agent May and replaced her with a Life Model Decoy. Aida's evil plans for May and the team remain a mystery.
On the heels of their encounter with Ghost Rider and battling the Watchdogs to their highest ranks, the Agents of S.H.I.E.L.D. find themselves in their most mind-bending mission yet. The heroes have been plugged into a virtual reality known as "The Framework," created by Dr. Radcliffe and Fitz. They awake to find themselves in an unrecognizable world – a world in which Hydra reigns supreme. What will become of the team as they make their way through this strange new landscape? What friends and foes will they face? And ultimately, will they ever escape and return to their real lives?
Former S.H.I.E.L.D. agent Daisy Johnson, now the vigilante "Quake", is hunting gang affiliates of the terrorist group Watchdogs in Los Angeles when Aryan Brotherhood members are murdered by the fiery "Ghost Rider". Agents Phil Coulson and Mack, who were forbidden from searching for Daisy by new S.H.I.E.L.D. Director Jeffrey Mace, are tipped off to her location by Agent Melinda May. Agent Leo Fitz discovers that S.H.I.E.L.D. ally Holden Radcliffe has created the android Aida, and agrees to help perfect her. He keeps this from his girlfriend Agent Jemma Simmons, who is in the Director's inner circle. Simmons discovers that Coulson and Mack are investigating Daisy, and orders May to stop them. The latter arrives to find them surveilling Chinese gangsters who bought a weapon off the Brotherhood: a mystical figure, who turns the gang members berserk, and secretly infects May as well. Daisy tracks down the Ghost Rider, but it defeats her. She later sees its human form, mechanic Robbie Reyes, looking after his disabled brother Gabe.
S.H.I.E.L.D. and Daisy independently investigate the figure, an apparent ghost of a woman named Lucy Bauer, both concluding that she worked at an abandoned facility, Momentum Energy. Daisy confronts Reyes again, and he once more overpowers her. Restraining her, Reyes searches Daisy's belongings and discovers her research on Momentum. He leaves, and Daisy escapes her restraints. As Mace plans to officially announce S.H.I.E.L.D. as a legitimate organization again, the infected May grows increasingly paranoid, seeing all people as monsters, and eventually attacking other agents. Mace restrains May with his Inhuman strength, and promises to take care of her. Mack and Fitz arrive at Momentum to find more ghosts, who attempt to blow it up with them inside. Ghost Rider intervenes, destroying one of the ghosts, and Daisy arrives to stop S.H.I.E.L.D. from taking him in. Rather than rejoin S.H.I.E.L.D., Daisy agrees to work with Reyes, who believes that the actions of the ghosts and Watchdogs may be tied to him.
Inhuman S.H.I.E.L.D. asset Elena Rodriguez is caught in a blackout in Miami. Reyes and Daisy are caught in another in Los Angeles. A group claiming to be the Inhuman resistance, fighting registration with the Sokovia Accords, take responsibility. Reyes explains that his uncle, Eli Morrow, was imprisoned for causing an explosion at Momentum that apparently created the ghosts; he believes that atoning for Morrow's sins will pay his debt to the Devil, and rid Reyes of the Ghost Rider. At the Reyes' house, Gabe realizes that Daisy is Quake and asks her to leave Robbie alone. Radcliffe and Simmons "cure" May by killing and reviving her. Coulson, Mack, and Fitz save Rodriguez from a group of Watchdogs, and find the EMP that caused the blackout—it was set off by the Watchdogs, who had access to S.H.I.E.L.D.'s list of registered Inhumans, and have backing from Senator Ellen Nadeer, whose brother Vijay is encased in an Inhuman terrigen cocoon. Hoping to assuage public fears of the Inhumans, Mace announces the return of S.H.I.E.L.D.
Daisy coerces Simmons to help track the Watchdogs' actions, discovering that the group hacked the Inhuman list using an Inhuman's monitoring device. Coulson visits Morrow in prison, but gets no answers. Reyes arrives to talk to Morrow, and Mack recognizes him as the Ghost Rider; they capture Reyes and earn his trust. He visits Morrow, and learns that the Momentum explosion was caused by a group of scientists studying the Darkhold, a mysterious book. Only Lucy's husband Joseph, whom Morrow had put in a coma trying to stop the experiments, survived. Daisy and Simmons find the next Inhuman on the list, J.T. James, and destroy his monitor, but he betrays them—he hates being an Inhuman and is aiding the Watchdogs. Coulson and Mack, alerted by the monitor's destruction, arrive to save Daisy and Simmons. The Ghost Rider defeats James. They then get May to help find the Darkhold. Aida supervised May's recovery as a Turing test by Radcliffe, but Simmons deduces her true nature, while being set to take a lie-detection test for Mace.
Lucy uses her ghostly state to wake Joseph and ask where he hid the Darkhold. Coulson arrives, and is able to learn of this before Joseph dies from her 'infection'. Coulson decides to use Morrow against Lucy, but doesn't tell Mace. The latter, whose public approval was high after heroics during a bombing in Vienna, becomes more popular after he reveals his Inhuman status in a television debate with Nadeer. However, Simmons threatens to reveal the truth about his Vienna actions, and he agrees to exempt her from any lie-detection tests. At the prison, Lucy infects the staff, who attack Coulson and May. Daisy saves them while Mack and Reyes break Morrow out. Reyes confronts the last member of the "Fifth Street Locos" gang who had paralyzed Gabe in a paid hit. Reyes loses control, and the Ghost Rider kills the prisoner. This allows Lucy to kidnap Morrow, whose help she needs. Mace secretly meets with Nadeer, and agrees to help her when she blackmails him with footage of the Ghost Rider's actions while working with S.H.I.E.L.D.
Mace sends Simmons on a secret assignment, then takes a team to board Coulson's plane and arrest Reyes and Daisy. The pair hide with a newly picked up Gabe, where Robbie explains that he and Gabe sneaked out to race in Morrow's car, but they were attacked by the Locos. Gabe was paralyzed and Robbie was killed. Robbie promised an unknown voice that he would seek vengeance if given a second chance, and was resurrected when the spirit of the Ghost Rider was passed to him by a stranger.[N 1] Mace finds the fugitives, but is overpowered by the Ghost Rider. He agrees to use Robbie against Lucy, and Fitz tracks her to an abandoned Roxxon power plant. May takes and hides the Darkhold while Robbie destroys Lucy, after the latter reveals that Morrow craves the Darkhold's power himself—his own experiments created the ghosts, and Joseph had ordered the hit on Morrow's car to stop him. Morrow now uses an improved version of the Momentum machine to gain the power to create matter. Robbie, Fitz, and Coulson disappear.
Coulson, Fitz, and Reyes are trapped between dimensions, and helplessly watch as Morrow kills several agents and escapes. Fitz overhears Mace arguing with Nadeer; he needs Simmons to understand Morrow's technology, but she has been taken to Nadeer's brother, who she helps escape from his terrigen cocoon. In Simmons' absence, Radcliffe studies the technology, and is presented with the Darkhold by May in her desperation to save Coulson. Radcliffe believes the book contains too much knowledge for a person to process, but Aida is able to read it, revealing her android nature to Coulson and May. Aida constructs a portal through which Coulson and Fitz return. During this time, the Ghost Rider spirit had left Reyes and possessed Mack to avoid the other dimension, where it had been before. Reyes confronts the spirit, promising to serve it even after they defeat Morrow if it leaves Mack. It agrees, and Reyes returns with it through the portal. Secretly, Aida begins experimenting with her new knowledge from the Darkhold, creating an artificial brain.
Coulson tells Mace that Aida is an android and he agrees to use her in the fight against Morrow. He also approves a strike team consisting of Rodriguez, Reyes, and Daisy, as long as the latter two keep a low profile. The team attempts to enter an abandoned building in which Morrow has barricaded himself via his growing abilities but, at first, only Reyes can make it through Morrow's initial trap. By viewing Reyes' body-cam, Fitz deduces that Morrow is drawing his power from the other dimension and has created a demon core that could destroy half the city if activated. Aida creates a new dimensional portal beneath the demon core, through which the device and Morrow are dragged. Reyes also falls through the portal after using the Ghost Rider to hold Morrow in place. Daisy is seen by local media and Mace publicly clears her name, reinstating her as an agent of S.H.I.E.L.D. He then allows Radcliffe to continuing working on his Life Model Decoy (LMD) program after his success with Aida, who has secretly replaced May with an LMD.
Fitz and Radcliffe are sent to clear Aida's memory of the Darkhold, but she reveals her new-found sentience and overpowers them. Taking control of S.H.I.E.L.D.'s systems, Aida finds the Darkhold after Coulson gives its location to the May LMD (which doesn't know it isn't the real May). Fitz is able to take control of the systems before Aida escapes and Mack beheads her. Radcliffe later laments about this to a new model of Aida, as he had programmed the original's apparent sentience in an attempt to steal the Darkhold for himself. Senator Nadeer orders a group of Watchdogs to kill a now recovered Vijay, but he convinces her to spare him as his long terrigenesis appears not to have affected him. Simmons, having identified Vijay from photographs, arrives with Mace and Daisy, as Vijay discovers he now has super-reflexes. Ellen convinces him to leave with her, but then shoots him in the stomach. Ellen asks the Watchdogs for reinforcements from "The Superior" as Vijay's body is dropped into a lake and enveloped by another terrigenesis cocoon.
Mace holds a press conference for Daisy, celebrating her "undercover" actions, until a sniper attempts to assassinate him. Coulson and Mack escort Mace and PR agent Burrows—who is often seen near Mace with a mysterious briefcase—to a quinjet, but it explodes mid-flight. Burrows is flung from the plane with the briefcase and the others crash land in a forest. There, they find ex-Hydra agents, hired by the Watchdogs, who have recovered Burrows' body. In the ensuing fight, Mace tries to get a serum from the briefcase, but it is destroyed and he is injured. Mace explains that he is not an Inhuman and that he was given his abilities by a super-serum from the government to create a trustworthy, enhanced leader of S.H.I.E.L.D. After their rescue by Daisy and the May LMD, Coulson tells Mace to continue as "the Patriot", the face and political leader of S.H.I.E.L.D, while Coulson takes back command of operations. The May LMD discovers her robotic skeleton from a wound and Fitz secretly begins studying Aida's severed head.
Daisy and Mace attend a Senate hearing to ratify the former's signing of the Sokovia Accords, with Senator Nadeer questioning Daisy's undercover actions. Coulson and Rodriguez infiltrate Nadeer's office to install surveillance devices, but are caught, giving Nadeer an excuse to start a full investigation of S.H.I.E.L.D. The May LMD realizes that she subconsciously leaked the details of Coulson's plan and confronts Radcliffe, as Fitz discovers Radcliffe's treachery from the original Aida's programming. Radcliffe explains to the LMD that her programming will not allow her to reveal her nature to anyone else, just before S.H.I.E.L.D. arrives and arrests him. Fitz later confronts Radcliffe in his cell and deduces that he is also an LMD—the real Radcliffe sought protection from Nadeer after Aida's initial failure. He and Aida have May captive with them, her mind in a virtual reality simulation of a tragic past event. Meanwhile, Mack and Rodriguez have grown close and he tells her of his daughter Hope from a past marriage who died as an infant.
Agent Billy Koenig, whom Coulson entrusted with the Darkhold, is abducted by the Watchdogs. Nadeer directs Radcliffe to the Superior, reclusive industrialist Anton Ivanov, and Radcliffe scans Koenig's brain to learn that the Darkhold was hidden in the Labyrinth, a S.H.I.E.L.D. facility known only to the Koenig family. Coulson secures the rest of the Koenig family, who take him, the May LMD, and Daisy to get the book. The Radcliffe LMD reveals that Radcliffe knows Fitz's estranged father and has created another LMD. Simmons remembers that Radcliffe scanned May's brain when they were curing her of Lucy's influence and warns Daisy of the May LMD in time to stop it from taking the Darkhold and killing Coulson. The Watchdogs arrive with Billy and Radcliffe steals the Darkhold in the ensuing fight. S.H.I.E.L.D. later destroys the remains of the first Aida and the Radcliffe LMD. Ivanov explains to Radcliffe that he plans to use the Darkhold to destroy both the Inhumans and the man who appears to be behind the recent alien crises—Coulson.
Coulson and Mack locate Agnes Kitsworth, Radcliffe's former lover and partner. Radcliffe left Kitsworth after she was diagnosed with terminal cancer, and modeled Aida after her. Coulson convinces Kitsworth to meet with Radcliffe. In case Nadeer is an Inhuman like her brother, Ivanov sends Watchdog Tucker Shockley to expose her to terrigen (provided by Radcliffe), but the substance transforms him instead. Shockley explodes, killing Nadeer, and then his molecules reassemble. Ivanov agrees to use Shockley's new ability against S.H.I.E.L.D. Radcliffe meets with Kitsworth and convinces her he can save her life if she escapes with him before S.H.I.E.L.D. captures them. Daisy confronts Shockley, and distracts him long enough for Fitz and Simmons to contain him in a specially-made device. Ivanov uses this as a distraction to attack and kidnap Mace, who has learned that each time he uses his super-serum there is a chance that it will kill him. As Kitsworth dies of the cancer, Radcliffe places her consciousness in the virtual "Framework" with May.
Years ago, Coulson and May recovered an unknown object from a Russian outpost, besting an SVR team that included Ivanov. For the failure, the SVR agents other than Ivanov were tortured and killed. Now, Ivanov leads S.H.I.E.L.D. on a treasure hunt around the world, including to that outpost, in their search for Mace. Ivanov has been torturing Mace, disgusted at his attempts to emulate the Inhumans. The team eventually finds Ivanov, and Daisy overpowers him. Coulson and Mack save a near-death Mace while Fitz and Simmons attempt to locate any sign of the Framework in hopes of finding May. Unsuccessful, the pair reunite with the others and they return to base. Aida, whom Radcliffe has left to carry out his plans while he spends time in the Framework, finds a crippled Ivanov. At base, Fitz and Simmons are alerted by their LMD security system, learning that four agents were replaced with LMDs by Aida while Fitz and Simmons were separated from the group. This includes Coulson, as the Coulson LMD wakes the May LMD from storage.
The new LMDs are aware of their nature, and plan to carry out Ivanov's goal of destroying all Inhumans. Simmons discovers that Mace, Mack, and Fitz are the other new LMDs, and overpowers Fitz. Daisy also discovers them, and plans with Simmons to hack into the Framework remotely to find the others from the inside. Aida kills Radcliffe's body, but lets his consciousness live in the Framework. Daisy overpowers the Mace, Mack, and Coulson LMDs, but they find the May LMD waiting for them at the base entrance, tasked with detonating a large explosive to prevent their escape. The May LMD instead lets them leave, and destroys the base with the LMDs inside. In the Framework, the agents find an altered reality: Daisy is in a relationship with an alive Grant Ward; Coulson is teaching about Inhumans; Hope is alive with Mack; Fitz is rich; Simmons is dead; and May works for Hydra, which has replaced S.H.I.E.L.D. In the real world, Aida is able to sever Ivanov's living head from his crippled body and builds android bodies for his mind to control.
In the Framework, Daisy discovers that she and Ward are agents of Hydra, working under May and Fitz. The tragic event from May's past has no longer happened; in the real world, she killed a young Inhuman girl but, in the Framework, she brought the girl back to the United States as a refugee who then became a mass murderer and the catalyst for Hydra to take power. Simmons awakens in a mass grave of S.H.I.E.L.D. agents and eventually comes across Coulson, who is teaching a Hydra-approved curriculum that warns against the dangers of Inhumans. Simmons is unable to convince Coulson that he is inside a virtual simulation and he calls Hydra. Daisy races to find Simmons before the rest of Hydra and is followed by Ward, who reveals himself to be a mole inside Hydra for the Resistance. Daisy and Simmons try to exit the Framework using a safeguard the latter created, but it has been blocked by Aida, who has entered the Framework as the Director of Hydra and Fitz's lover. Daisy then goes to Coulson and he remembers her name.
Hoping Radcliffe can help them escape, Daisy returns to Hydra and locates him, but May gives her a new mission on the orders of Fitz and Aida, the latter choosing to go by Ophelia, or Madame Hydra. Ward directs Coulson (who can remember some things, thanks to previous tampering with his mind) and Simmons to the Resistance, the remnants of S.H.I.E.L.D. under the command of an Inhuman Mace. Ward, Simmons, and Coulson take a stolen Hydra quinjet to extract Radcliffe. May and Daisy arrest Mack, and May forces him to trick Daisy into confessing her true allegiance. The others find Radcliffe living in seclusion with Kitsworth, and he explains that he and Kitsworth cannot leave the Framework due to their real bodies having died. Fitz and Madame Hydra arrive, and Radcliffe attempts to appeal to Fitz, though Fitz already knows of the "other world" and that Radcliffe had enslaved Aida there. He kills Kitsworth and imprisons Radcliffe, torturing him and Daisy. Regretting his actions, Mack joins the Resistance.
Mace and Coulson infiltrate a Hydra "Enlightenment Camp" to free an undercover agent—Antoine Triplett, a S.H.I.E.L.D. agent who died in the real world. They are tracked there by May, who uses a super serum to fight Mace. Through the vents in their holding cells, Daisy learns from Radcliffe of a backdoor he installed to escape the Framework that Aida is unable to disable. Coulson attempts to save one of his former students who he sees being held in the camp, and Mace follows him into a building to help. Hydra uses a missile to bring the building down, and May enters the rubble to ensure Mace is dead. She finds him stopping debris from crushing the student, with Coulson and Triplett helping other children escape the building. May is horrified to find children being victimized by Hydra. With the others having escaped to safety, Mace is crushed beneath the debris, and in the real world Aida finds his physical body dead as well. Turning on Hydra, May sneaks a Terrigen crystal to Daisy so she can gain her Inhuman abilities within the Framework.
May and Daisy escape Hydra, with Daisy using her abilities to break Ophelia's back. Ophelia insists that Fitz complete work on their secret Project: Looking Glass, after which her Framework body will no longer matter. May and Daisy join up with S.H.I.E.L.D., who are struggling to regroup after Mace's death. May provides them with body cam footage from the attack on the Enlightenment Center, which Coulson broadcasts to the world to counteract Hydra's propaganda. Meanwhile, Simmons and Triplett investigate a Russian oil platform which he believes is the location of Looking Glass from his time undercover; the platform is the Framework equivalent of Ivanov's oil platform in the real world, from where Aida is running the Framework. The pair find the platform empty, and Simmons deduces that Looking Glass consists of a machine built on the real world platform, to be connected to a machine in the Framework using knowledge from the Darkhold, allowing Ophelia to go from the Framework to a true human body in the real world.
After Daisy and Simmons entered the Framework, their bodies were protected by Rodriguez aboard the S.H.I.E.L.D. aircraft Zephyr One. With their connection to the Framework draining the plane's power, Rodriguez chose to shut off its cloaking ability, revealing their location to Ivanov and his men. In the Framework, Simmons visits and accidentally kills Fitz's father Alistair, and Fitz begins hunting her with help from Radcliffe, Fitz having offered to send Radcliffe through the machine, restoring his living body. Ophelia initiates her transference into her new body. Daisy takes the group to Radcliffe's exit point, where she, Coulson, and May cross back into the real world. Fitz arrives and confronts Simmons, but is overpowered by Radcliffe, who regrets all his actions since he first saw and wanted the Darkhold. Radcliffe sends Fitz through, followed by Simmons. Mack decides to stay, not wanting to live in a world without Hope. At Ivanov's platform, the newly human Ophelia confronts Coulson, May, and Fitz, teleporting away with the latter.
The agents on Zephyr One fight off Ivanov's men and race to the platform to save Coulson and May from Ivanov's android bodies. Ivanov launches torpedoes at the platform that threaten Mack's body, but the latter is saved by Ophelia, convinced by Fitz to put to good use the Inhuman abilities his machine had given her new body. In isolation at S.H.I.E.L.D., Fitz and Ophelia discuss her newly discovered human emotions and the fact that he remembers all the terrible things he did inside the Framework. He admits that he ultimately still loves Simmons over her, outraging Ophelia. Talbot arrives at the ruined S.H.I.E.L.D. base, where Ophelia kills several of his soldiers and other S.H.I.E.L.D. agents. Coulson and the others flee in the Zephyr once more, while Ophelia returns to Ivanov, who plans to use knowledge from the Darkhold to apply the changed reality of the Framework to the real world. Meanwhile, Rodriguez enters the Framework herself to try convince Mack to leave, and the Ghost Rider returns through a portal from the other dimension.
Ivanov takes the Darkhold to an international meeting on S.H.I.E.L.D. and the recent events. He proposes to use the book against the Inhumans, which is timed with an attack on the group by an LMD of Daisy, who shoots Talbot in the head leaving him comatose. In the ensuing fight, S.H.I.E.L.D. is able to retrieve the Darkhold with Reyes' help. In the Framework, Rodriguez is unable to convince Mack to leave, but he returns with her after Hope's code is deleted as a result of Ophelia shutting down the Framework. Radcliffe is also deleted, after accepting that immortality without Kitsworth is worthless. Ophelia comes for the Darkhold, and Coulson surprises her by unleashing the Spirit of Vengeance himself, having made a deal to become the Ghost Rider for a short time. He incinerates Ophelia. Reyes, now the Ghost Rider again, takes the Darkhold through a portal. The S.H.I.E.L.D. agents then wait to be arrested by the government, but are instead taken by a mysterious group. Some time later, Coulson finds himself on a space station.
- Clark Gregg as Phil Coulson / Phil Coulson LMD
- Ming-Na Wen as Melinda May / Melinda May LMD
- Chloe Bennet as Daisy Johnson/Quake/Skye / Daisy Johnson LMD
- Iain De Caestecker as Leo Fitz/The Doctor / Leo Fitz LMD
- Elizabeth Henstridge as Jemma Simmons / Jemma Simmons LMD
- Henry Simmons as Alphonso Mackenzie / Alphonso Mackenzie LMD
- John Hannah as Holden Radcliffe / Holden Radcliffe LMD
- Gabriel Luna as Robbie Reyes/Ghost Rider
- Natalia Cordova-Buckley as Agent Yo-Yo Rodriguez
- Mallory Jansen as Aida / Agnes Kitsworth
- Lorenzo James Henrie as Gabe Reyes
- Lilli Birdsell as Lucy Bauer
- Briana Venskus as Agent Piper
- Max Osinski as Agent Davis
- Ricardo Walker as Agent Prince
- Blaise Miller as Agent Nathanson
- Jason O'Mara as Jeffrey Mace/Patriot / Jeffrey Mace LMD
- Ward Roberts as Hugo
- Usman Ally as Vincent
- Patrick Cavanaugh as Agent Burrows / Agent Burrows (Framework)
- Parminder Nagra as Senator Ellen Nadeer
- José Zúñiga as Eli Morrow
- Kerr Smith as Joseph Bauer
- Manish Dayal as Vijay Nadeer / Vijay Nadeer (Framework)
- John Pyper-Ferguson as Tucker Shockley
- Adrian Pasdar as Brigader General Glenn Talbot
- Zach McGowan as Anton Ivanov/Superior
- Brett Dalton as Grant Ward (Framework)
- Jordan Rivera as Hope Mackenzie (Framework)
- B.J. Britt as Antoine Triplett (Framework)
- David O'Hara as Alistair Fitz (Framework)
|The Ghost||4.01||September 20, 2016||Jed Whedon & Maurissa Tancharoen||Billy Gierhart|
|Ghost Rider is coming, and S.H.I.E.L.D. will never be the same.|
|Meet the New Boss||4.02||September 27, 2016||Drew Z. Greenberg||Vincent Misiano|
|Daisy goes to battle Ghost Rider at a terrible cost, and Coulson faces the new Director, and his bold agenda surprises them all.|
|Uprising||4.03||October 11, 2016||Craig Titley||Magnus Martens|
|As Coulson, Mack and Fitz attempt to track down and neutralize a rogue group looking to end Inhuman Registration worldwide, Simmons and Dr. Radcliffe only have hours to save May before she succumbs forever to her mysterious illness.|
|Let Me Stand Next to Your Fire||4.04||October 18, 2016||Matt Owens||Brad Turner|
|As Ghost Rider's quest for vengeance brings him into an explosive confrontation with S.H.I.E.L.D., Coulson and Mack must rely on an unlikely ally in their time of desperate need; and Daisy reunites with a familiar face to stop the Watchdogs.|
|Lockup||4.05||October 25, 2016||Nora Zuckerman & Lilla Zuckerman||Kate Woods|
|As Robbie Reyes struggles to control the Ghost Rider; S.H.I.E.L.D. infiltrates a high-security prison to unravel the secrets that haunt them all.|
|The Good Samaritan||4.06||November 1, 2016||Jeffrey Bell||Billy Gierhart|
|Robbie's shocking story on how he became Ghost Rider is finally discovered as Coulson and his team's lives hang in the balance.|
|Deals With Our Devils||4.07||November 29, 2016||DJ Doyle||Jesse Bochco|
|With the loss of half the team, the remaining members search for answers as the clock counts down for Ghost Rider.|
|The Laws of Inferno Dynamics||4.08||December 6, 2016||Paul Zbyszewski||Kevin Tancharoen|
|S.H.I.E.L.D. and Ghost Rider find themselves unlikely allies when the lives of all of Los Angeles hang in the balance.|
|Broken Promises||4.09||January 10, 2017||Brent Fletcher||Garry A. Brown|
|Coulson is unaware of a dark secret May is hiding, even as the two grow closer; Aida is determined to find the Darkhold.|
|The Patriot||4.10||January 17, 2017||Sharla Oliver & James C. Oliver||Kevin Tancharoen|
|Separated from their team, Coulson and Mack discover a shocking secret about Mace, leaving all of S.H.I.E.L.D. in a precarious position.|
|Wake Up||4.11||January 24, 2017||Drew Z. Greenberg||Jesse Bochco|
|May works to uncover the truth about what happened to her; Aida's next move puts everyone's life at risk.|
|Hot Potato Soup||4.12||January 31, 2017||Craig Titley||Nina Lopez-Corrado|
|Agents Sam and Billy Koenig are hunted down to get at the Darkhold book, and only Phil Coulson and the team can save them before the clock ticks out.|
|BOOM||4.13||February 7, 2017||Nora Zuckerman & Lilla Zuckerman||Billy Gierhart|
|Daisy, Director Mace and the S.H.I.E.L.D. team must find a way to contain an explosive Inhuman. Meanwhile, Coulson and Mack come face-to-face with Radcliffe’s inspiration for Aida.|
|The Man Behind the Shield||4.14||February 14, 2017||Matt Owens||Wendey Stanzler|
|Mace fights for his life while Coulson and team find themselves in a deadly cat-and-mouse game as they attempt his rescue.|
|Self Control||4.15||February 21, 2017||Jed Whedon||Jed Whedon|
|Suspicion turns to paranoia when the team doesn’t know who can be trusted as more LMDs infiltrate S.H.I.E.L.D.|
|Agents of HYDRA|
|What If...||4.16||April 4, 2017||DJ Doyle||Oz Scott|
|Daisy and Simmons uncover secrets and lies in a world gone mad. With HYDRA in control, they are our only hope to save everyone.|
|Identity and Change||4.17||April 11, 2017||George Kitson||Garry A. Brown|
|As Daisy and Simmons struggle to discover an escape route to the real world, the identity of the Inhuman leader of the Resistance is revealed.|
|No Regrets||4.18||April 18, 2017||Paul Zbyszewski||Eric Laneuville|
|The truth behind Fitz's turn could bring down all of S.H.I.E.L.D..|
|All the Madame's Men||4.19||April 25, 2017||James C. Oliver and Sharla Oliver||Billy Gierhart|
|Daisy finds herself teamed up with an unlikely partner. Meanwhile, Aida prepares to put her ultimate end game into effect.|
|Farewell, Cruel World!||4.20||May 2, 2017||Brent Fletcher||Vincent Misiano|
|The clock is ticking for Daisy and Simmons to get the team out of the Framework, but not everyone is ready and willing to leave.|
|The Return||4.21||May 9, 2017||Maurissa Tancharoen and Jed Whedon||Kevin Tancharoen|
|Coulson and the team's victory in the Framework is short-lived, as an even deadlier enemy looms against them all.|
|World's End||4.22||May 16, 2017||Jeffrey Bell||Billy Gierhart|
|With the surprising emergence of Ghost Rider, Coulson and the team attempt to stop Aida from ending the world.|
- This is the first season where Brett Dalton doesn't reprise his role as Grant Ward.
- This is the first season of Agents of S.H.I.E.L.D. where the Kree don't appear.