Spider-Man: No Way Home's plot hinges on several major spoilers. The central twist is the return of previous Spider-Man actors Tobey Maguire and Andrew Garfield, who are pulled into the MCU after Ned Leeds accidentally opens portals with Doctor Strange's Sling Ring. Their appearance transforms the film into a multi-generational team-up, where the three Peters share their grief and wisdom, ultimately working together to cure the villains.
A pivotal and tragic turn is the death of Aunt May at the hands of the Green Goblin. She is killed by his glider after he attacks Peter in Happy's apartment building. Her final words to Peter, "With great power, there must also come great responsibility," firmly establish her as the MCU's 'Uncle Ben' figure, providing the definitive moral lesson that shapes Peter's destiny. This loss fuels Peter's rage, and he nearly kills the Goblin in the final battle, only to be stopped by Tobey Maguire's Peter, who is then stabbed himself (though he survives).
The film's ending is perhaps its biggest revelation. To stop the multiverse from collapsing completely, as beings from every universe who know Peter Parker is Spider-Man begin to break through, Peter asks Doctor Strange to cast a final, corrected spell: make everyone, everywhere, forget who Peter Parker is. This includes MJ, Ned, Happy, and the Avengers. The spell works, and Peter is left completely alone and anonymous in the world. In the final scenes, he visits MJ and Ned, who do not recognize him, and chooses not to reintroduce himself to protect them. He then creates a simple, homemade suit and resumes his life as a solitary, street-level hero, fully embracing his identity as Spider-Man at the cost of his entire personal life.
The post-credits scene reveals Eddie Brock/Venom (from the Sony universe) being transported back to his reality by Strange's spell, but leaving behind a small piece of the symbiote, teasing a future confrontation between the MCU's Spider-Man and Venom.