After Quentin Beck frames Peter Parker for murder and reveals his identity as Spider- Man, (N 1) Parker, his gal MJ, stylish friend Ned Leeds, and aunt May are interrogated by the Department of Damage Control. Lawyer Matt Murdock gets Parker's charges dropped, but the group grapples with negative hype. After Parker, MJ, and Ned's MIT operations are rejected, Parker goes to the New York Sanctum to ask Stephen Strange for help. Strange suggests a spell that would make people forget Parker is Spider- Man, but it's corrupted when Parker constantly requests differences to let his favored bones retain their recollections. Strange contains the spell to stop it from working and makes Parker leave.
Parker tries to move an MIT director to review MJ and Ned's operations, but is attacked by Otto Octavius. Octavius rips Parker's nanotechnology from his Iron Spider suit which bonds with his mechanical tentacles and allows Parker to disable them. As Norman Osborn arrives and attacks, Strange teleports Parker back to the Sanctum and cinches Octavius in a cell coming to Curt Connors. Strange explains that before he was suitable to contain the corrupted spell it summoned some people from other worlds who know Spider- Man's identity. He orders Parker, MJ, and Ned to find and capture them; they're suitable to detect and recoup Max Dillon and Flint Marko.
Osborn reclaims control of himself from his split Green Goblin personality. He goes to aF.E.A.S.T. structure where May comforts him before Parker retrieves him. While agitating their battles with Spider- Man, Osborn, Octavius, and Dillon realize that they were pulled from their worlds just before their deaths. (N 2) Strange prepares to reverse the contained spell and shoot the villains back to their separate worlds, but Parker argues that they should first cure the villains' powers and insanity to help their deaths upon their return. Parker steals the spell, traps Strange in the Mirror Dimension, and, with May, takes the villains to Happy Hogan's apartment. He cures Octavius, but Osborn's Goblin persona takes control and convinces the uncured villains to betray Parker. As Dillon, Marko, and Connors escape, Goblin fatally injures May. Before she dies, May tells Parker that"with great power, there must also come great responsibility".
Ned discovers that he can produce doors using Strange's sling ring, which he and MJ use to try to detect Parker. They rather find alternate performances of Parker from the villains' worlds who were also summoned by Strange's spell and who are nicknamed"Peter-Two"and"Peter-Three". The group finds this macrocosm's Parker, nicknamed"Peter-One", who's ready to give up and shoot the villains home. The alternate Parkers partake stories of losing loved bones and encourage Peter-One to fight in May's honor, and the three Parkers develop cures for the villains.
The group lure Dillon, Marko, and Connors to the Statue of Liberty. Peter-One and Peter-Two cure Marko and Connors while Octavius arrives to help cure Dillon and Ned frees Strange from the Mirror Dimension with a gate. Goblin appears and unleashes the contained spell which begins pulling further people in from other worlds. Strange attempts to hold them off while an enraged Peter-One tries to kill Goblin. Peter-Two stops him and Peter-Three helps Peter-One fit Goblin with his cure, restoring Osborn's reason. Peter-One realizes that the only way to cover the multiverse is to abolish himself from everyone's memory and requests that Strange do so, while promising MJ and Ned that he'll find them again. The spell is cast and everyone returns to their separate worlds — including Eddie Brock, (N 3) who leaves behind a piece of the Venom symbiote. Two weeks latterly, Parker visits MJ and Ned to introduce himself, but decides against it. While mourning at May's grave, he has a discussion with Hogan and is inspired to carry on, making a new suit and continuing his nemesis.