Peter Parker’s life is thrown into chaos after J. Jonah Jameson publicly reveals that Peter is Spider-Man and falsely accuses him of murdering Mysterio during the London drone attack. As crowds swarm Peter and his girlfriend MJ outside their school, the two struggle to escape the media frenzy and police pursuit. Peter returns home with MJ to reunite with Aunt May and Happy Hogan, who reveal they recently ended their relationship. Soon afterward, the Department of Damage Control arrests Peter, MJ, Ned Leeds, and Happy for questioning regarding Mysterio’s death and Stark technology. Attorney Matt Murdock successfully gets Peter’s criminal charges dismissed, but Peter’s public reputation remains ruined. The controversy surrounding Spider-Man causes MIT to reject Peter, MJ, and Ned despite their excellent academic records.

Desperate to fix the damage done to his friends’ futures, Peter seeks help from Doctor Strange at the New York Sanctum. Strange agrees to cast a spell using the Runes of Kof-Kol that will make the entire world forget Peter Parker is Spider-Man. However, during the spell, Peter repeatedly interrupts Strange by asking for certain people—such as MJ, Ned, and Aunt May—to still remember him. The constant changes destabilize the spell, forcing Strange to contain it before it tears reality apart. Furious that Peter never simply appealed to MIT directly, Strange throws him out of the Sanctum. Peter later tracks down an MIT administrator traveling across the Alexander Hamilton Bridge to plead for reconsideration of his friends’ applications. Before he can finish speaking, Peter is suddenly attacked by Doctor Otto Octavius, also known as Doctor Octopus, who somehow recognizes him as Spider-Man despite never having met this version of Peter. During the battle, Doc Ock tears nanotechnology from Peter’s Iron Spider suit and unintentionally allows Peter to seize control of his mechanical tentacles. Peter saves the MIT administrator from falling off the bridge, earning her gratitude and a promise to reconsider the applications.

Moments later, the Green Goblin attacks the bridge with explosive pumpkin bombs before Doctor Strange teleports Peter and Doctor Octopus back to the Sanctum. Strange explains that Peter’s failed spell accidentally opened fractures in the multiverse, pulling in individuals from alternate universes who know Spider-Man’s identity. Strange reveals he has already captured several intruders, including the Lizard. He tasks Peter with helping locate the remaining visitors so they can be returned to their original universes before the multiverse destabilizes further. Using a magical device called the Macchina di Kadavus to contain the broken spell, Strange equips Peter with a mystical upgrade to his suit and sends him to track the remaining villains.

With help from MJ and Ned, Peter locates Electro at a power station outside the city. Electro attacks Spider-Man and absorbs massive amounts of electricity, evolving into a more stable and powerful form. Sandman briefly aids Peter during the fight before both villains are captured and taken to the Sanctum. Elsewhere, Norman Osborn struggles against the violent Green Goblin personality and eventually destroys his Goblin mask before wandering into a F.E.A.S.T. shelter run by Aunt May. Peter brings Osborn back to the Sanctum, where the villains gradually realize they were pulled from their universes moments before dying while fighting Spider-Man. Doctor Octopus recalls sacrificing himself in the river during the fusion reactor disaster, while Electro remembers dying inside a power grid. Strange coldly explains that returning them home means they will resume their fates and likely die. Peter, horrified by the idea of sending them back to death, believes they deserve a chance at redemption instead.

Ignoring Strange’s warnings about the dangers to the multiverse, Peter steals the Macchina di Kadavus and traps Strange inside the Mirror Dimension after using geometry to outsmart him. Peter frees the villains and brings them to Happy Hogan’s condominium, where he begins developing cures for their conditions using Stark technology. He successfully repairs Doctor Octopus’ inhibitor chip, restoring Otto’s sanity and freeing him from the influence of the tentacles. Peter also develops cures for Electro, Sandman, Lizard, and Green Goblin. However, before Norman can be cured, the Green Goblin personality fully takes over and manipulates Electro into rejecting his cure. Goblin steals an Arc Reactor to increase Electro’s power, destroys the apartment building, and brutally attacks Peter. During the chaos, the villains escape while Aunt May attempts to help Peter stop Goblin. After Norman appears cured momentarily, the Goblin suddenly attacks again, impaling May with his glider and throwing explosive pumpkin bombs into the building. Peter finds May badly injured in the rubble. As she dies in his arms, she tells Peter the words that define Spider-Man forever: “With great power, there must also come great responsibility.”

Devastated by May’s death and overwhelmed with guilt, Peter disappears while Jameson continues blaming Spider-Man for the destruction. Concerned for him, Ned accidentally opens magical portals using Doctor Strange’s Sling Ring while trying to locate Peter. Instead, he summons another Spider-Man from a different universe—the Peter Parker who previously battled the Lizard and Electro. Attempting again, Ned accidentally summons yet another Spider-Man, the older Peter Parker who once fought Green Goblin, Doctor Octopus, and Sandman. The two alternate Spider-Men eventually locate the grieving Peter atop a rooftop and comfort him by sharing their own experiences with loss and regret. Inspired by their words, Peter recommits himself to curing the villains instead of killing them.

The three Spider-Men work together in a Midtown High laboratory to complete cures for the villains. The older Peter develops a cure for Norman Osborn, while the younger Peter from the other universe recreates the Lizard antidote. Once finished, the Spider-Men lure the villains to the Statue of Liberty, where Captain America’s shield is being added during renovations. A massive battle erupts across the scaffolding as Electro, Sandman, and Lizard attack. Initially struggling to coordinate, the Spider-Men eventually work together effectively after Peter explains his experience fighting alongside the Avengers. One by one, they cure Sandman and Lizard, while Doctor Octopus unexpectedly arrives to help neutralize Electro by removing the Arc Reactor powering him.

As Doctor Strange returns to contain the collapsing multiverse, Green Goblin launches a final attack and destroys the Macchina di Kadavus, causing rifts in reality to open across the sky. Figures from countless universes begin trying to break through into Peter’s world. During the chaos, MJ falls from the Statue of Liberty after being knocked off the scaffolding. Peter dives to save her but is intercepted by Goblin. The alternate Peter from another universe catches MJ instead, redeeming himself after failing to save Gwen Stacy years earlier.

Enraged by May’s death, Peter viciously attacks Green Goblin and nearly kills him using the Goblin Glider before the older Peter stops him. Goblin then stabs the older Peter in the back, though the injury is not fatal. The younger alternate Spider-Man gives Peter the cure for Norman Osborn, allowing him to finally free Norman from the Goblin persona. With the multiverse continuing to collapse, Peter realizes the only solution is for Doctor Strange to cast a new spell making everyone in the world forget Peter Parker entirely. Though it will erase Peter from the memories of MJ, Ned, Happy, and everyone else he loves, Peter accepts the sacrifice to save reality.

Peter says emotional goodbyes to the two alternate Spider-Men before Strange casts the spell. The cracks in the multiverse close, sending the villains and Spider-Men back to their home universes fully cured. Weeks later, Peter attempts to reconnect with MJ and Ned but ultimately chooses not to remind them who he is after seeing them beginning happy new lives at MIT. Peter visits Aunt May’s grave, where he quietly meets Happy Hogan, who no longer remembers him either. Accepting his new reality, Peter moves into a small apartment, studies for his GED, and creates a new homemade Spider-Man suit before swinging back into New York City alone, embracing Aunt May’s lesson about responsibility.

In a post-credits scene, Eddie Brock and the alien symbiote Venom are abruptly returned to their universe after briefly visiting the MCU during Strange’s broken spell. However, a small fragment of the symbiote is accidentally left behind in the MCU timeline.