After defending the New York Sanctum from Kaecilius and fighting Lucian Aster in the Astral Dimension, Stephen Strange was selected by the Ancient One to replace Daniel Drumm, who was killed during the battle, as the Sanctum's protector.
Strange, however, refused, citing that he took an oath to save lives and that his involvement in Aster's death went against everything he swore to do as a doctor. When the Ancient One claimed he was still set on feeding his inflated ego, Strange shot back by alluding to her drawing power from the Dark Dimension, which he learned from Kaecilius.
While Karl Mordo outright denied Strange's accusation, the Ancient One remained silent and warned Strange to choose his next words carefully before leaving. The two men started to argue only to hear Kaecilius and the remaining Zealots entering the Sanctum.
As Kaecilius prepared to destroy the New York Sanctum, Doctor Strange attempted to contain the situation by trapping everyone in the Mirror Dimension. Kaecilius, however, revealed that his connection to Dormammu enhanced his abilities while in the Mirror Dimension.
Realizing he made a grave error, Strange stole Kaecilius' Sling Ring and fled the Sanctum with Karl Mordo. Strange then used the Sling Ring to conjure a portal only for Kaecilius to distort gravity and make him lose focus. The Zealots proceeded to pursue the two Masters throughout New York City, twisting the landscape to the point where it was unrecognizable.
Despite Kaecilius' best efforts to kill them, Strange and Mordo successfully countered his attacks with help from the Cloak of Levitation and the Vaulting Boots of Valtorr. The lead Zealot eventually managed to separate the two and began chasing after Strange while his remaining followers pursued Mordo. Using the changing landscape to his advantage, Kaecilius cornered Strange, pinned him to the ground, and reclaimed his Sling Ring.
Kaecilius was about to kill Strange when the Ancient One appeared and used her powers to create a battle arena out of subway station walls, causing the Dark Dimension's symbol to be burned on her forehead. As a horrified Mordo realized that Strange had been telling the truth, the Ancient One tried to convince Kaecilius that she was attempting to save him from himself by not revealing her secret.
Kaecilius, however, refused to believe his former mentor and ordered the Brunette and Tall Zealots to attack. He then watched the Ancient One fight his followers and waited until she was fighting the Tall Zealot before conjuring a Space Shard.
Quietly approaching his former mentor, Kaecilius used the Space Shard to stab her through his follower and mortally wounded the combatants. Satisfied by his actions, Kaecilius proceeded to throw the Ancient One out of the Mirror Dimension, where she fell several hundred stories to the ground below.
Escaping from the Mirror Dimension, Doctor Strange and Karl Mordo took the Ancient One to Metro-General Hospital, where Strange worked with Christine Palmer and Nicodemus West in an attempt to save her life. As Palmer and West started operating, however, Strange's astral form was forced out of his body. Unable to understand what was going on, Strange made his way through the hospital until he found the Ancient One's astral form standing on a balcony overlooking New York City. Strange tried convincing her to return to her body but she refused, confessing that she always knew this would be the exact moment of her death.
The Ancient One proceeded to give Strange three last pieces of advice: that his arrogance and fear of failure kept him from true greatness; that, much like Jonathan Pangborn, he had to choose between returning to his old life or serving something greater than himself; and that, while Mordo would never understand why she drew power from the Dark Dimension, he needed Mordo's rule-abiding nature, just as Mordo needed his flexibility, to stop Dormammu.
After acknowledging that she was not ready to die despite her immortality, the Ancient One used her powers to manipulate time and watch the snow before disappearing from the Astral Dimension, causing her physical form to stop operating. Strange returned to his physical form before making amends with Christine and returning to Kamar-Taj.