Peter Parker plans to propose to Mary Jane Watson, who has just made her Broadway musical debut. Later, a meteorite lands at Central Park, and an extraterrestrial symbiote follows Peter to his apartment. Harry Osborn, seeking vengeance after his father’s death, attacks Peter with weapons based on his father’s Green Goblin technology. The battle ends in a stalemate, with Harry crashing out and developing amnesia, wiping out his memory of Peter as Spider-Man. Meanwhile, police pursue escaped prisoner Flint Marko, who visits his wife and dying daughter before fleeing again, and falling into an experimental particle accelerator that fuses his body with the surrounding sand, transforming him into the Sandman.
During a festival honoring Spider-Man, Peter kisses Gwen Stacy, infuriating Mary Jane. The superpowered Marko robs an armored car, and Peter confronts him. Marko easily subdues Peter, and escapes. NYPD Captain George Stacy informs Peter and Aunt May that Marko was Uncle Ben’s true killer; the deceased Dennis Carradine was Marko’s accomplice. While Peter sleeps in his Spider-Man suit, the symbiote assimilates his suit. Peter later awakens and discovers his costume changed and his powers enhanced; however, the symbiote also brings out Peter’s dark side. Wearing the new suit, Peter locates Marko and battles him in a subway tunnel. Discovering that water is Marko’s weakness, Peter breaks a water pipe, causing water to reduce Marko into mud, washing him away and believing him to be dead.
Peter’s changed personality alienates Mary Jane, whose career is floundering, and she finds solace with Harry, but leaves afterwards in regret. Harry recovers from his amnesia and, urged by a hallucination of his father, blackmails Mary Jane into unwillingly breaking up with Peter. After Mary Jane tells Peter she loves “somebody else”, Harry meets with Peter and claims to be “the other guy”. Peter confronts Harry about forcing Mary Jane to end her relationship with him and spitefully tells Harry that his father never loved him. Another battle ensues, in which Harry throws a pumpkin bomb at Peter, who deflects it back, disfiguring Harry’s face.