Two years after a spider bite endowed Peter Parker with super powers enabling him to thwart crime under the guise of his secret alter ego, Spider-Man, his life is in chaos. He has just lost his job as a pizza deliveryman, his grades are suffering at college, his part-time job selling photographs of Spider-Man to the Daily Bugle is faltering and the girl he loves, actress Mary Jane Watson, fears that he is too irresponsible for a relationship. At his birthday at his aunt May’s, Peter's best friend from high school, Harry Osborn, expresses resentment that Peter associates with Spider-Man because Harry is embittered that Spider-Man killed his father Norman after Norman's insanity turned him into the arch-criminal Green Goblin. The next day, Harry introduces Peter to his idol, noted scientist Dr. Otto Octavius, who is working on a revolutionary energy fusion project for OsCorp, Harry's company, which is supplying a small amount of the dangerous element tridium for his experiment. Octavius is impressed with Peter's scientific brilliance, and Peter spends a pleasant day with him and his wife Rosie. That night, Peter is determined to keep his promise to see Mary Jane in The Importance of Being Earnest , but arrives too late because he took time to assume his Spider-Man guise and prevent a crime. After the play, Peter is crushed to see Mary Jane kissing another man. Feeling miserable, Peter goes home and inexplicably has difficulty using his spider-like powers. The next day, Peter and Harry attend Octavius' experiment. With many dignitaries and the press watching, Octavius dons an apparatus consisting of four huge metal arms that are affixed to his spine. He then proceeds to create a fusion that he proclaims will solve the world's energy problems. Although the fusion causes a dangerous power spike, Octavius refuses to heed Harry and Peter’s warnings. Soon the metal arms seem to come alive and, despite Peter’s secretly donning his Spider-Man suit and attempting to stop the now out-of-control metal arms, the lab is destroyed and Rosie is killed. After the mayhem, Harry realizes that he is ruined, and blames Spider-Man, who actually saved Harry’s life. That night, as surgeons start to remove the metal arms now fused onto Octavius’ body, he and the arms suddenly awaken and kill the medical team. With the added appendages to aid him, Octavius quickly escapes to an abandoned building on the river. The next day, Octavius realizes that the arms are trying to control his thoughts but, despondent over the loss of Rosie, he succumbs to their taunts and determines to rebuild the experiment with money he will steal. Some time later, while Peter is at a bank unsuccessfully helping Aunt May refinance her house to save it from foreclosure, Octavius, now the evil “Doc Ock,” enters the bank, breaks open the vault and steals sacks of money. Although Peter quickly becomes Spider-Man, Doc Ock grabs the screaming Aunt May. Spider-Man and Aunt May soon affect her release, but Doc Ock escapes. That night,after J. Jonah Jameson, the testy editor of the Daily Bugle , gives Peter the assignment to photograph a society party honoring Jameson’s astronaut son John, Peter is crushed to see that John is Mary Jane’s date and the man who kissed her after the play. On the terrace, Mary Jane sadly accuses Peter of being an empty shell, then Harry, who is also at the party, drunkenly chastises him for being more loyal to Spider-Man than his best friend. After Mary Jane and John’s engagement is announced, a despondent Peter leaves and finds that his powers again are failing. Peter then dreams that his late uncle Ben is saying that his powers are a great gift, but Peter decides that he no longer wants those powers and throws his Spider-Man suit into a garbage can. Freed from the burden of being Spider-Man, Peter soon becomes happier and his grades improve. When he sees Mary Jane, she, too, notices the change, but is worried that it is only temporary. Meanwhile, a garbage man has brought the Spider-Man suit to Jonah, who runs a headline in the Daily Bugle proclaiming “Spider-Man No More.” Later, after Peter and Aunt May visit Uncle Ben’s grave, Peter confesses that he is the one responsible for Ben’s death at the hands of a car-jacker because earlier Peter had allowed the criminal to get away after robbing someone who had cheated Peter. Without saying a word, Aunt May goes to her room, leaving Peter alone and feeling guilty. That night, Doc Ock climbs to Harry’s penthouse and demands the rest of the tridium. Although initially refusing, warning that all of New York could be destroyed, Harry relents, on condition that Doc Ock bring Spider-Man to him. As Doc Ock departs, Harry tells him that he can find Spider-Man through Peter, but asks him not to hurt his friend. At the same time, while Peter is out walking, he sees a burning building and hears that a child is trapped inside. He immediately rushes into the building and saves the girl but, upon learning that someone else in the building burned to death, Peter feels responsible. While agonizing over his situation in his room, Ursula, his landlord’s daughter, offers him a piece of cake and delivers a message from Aunt May. The next day, he visits his aunt and learns that she is resolved to move into a small apartment and thinks that Peter is brave to have told her about Ben’s death. She also mentions that Henry Jackson, a young boy across the street, looks up to Spider-Man and wants to be just like his hero. Now determined to recapture his powers, Peter goes to the roof of his building to practice jumping and spinning webs, but has little success, despite his enthusiasm. When he later meets Mary Jane for coffee and she says that she believes that he has changed and wants to get back together, he lies that he does not love her. Just as she asks him to kiss her to prove it, a car crashes through the café, announcing the arrival of Doc Ock. After grabbing Mary Jane in one of his mechanical arms, Doc Ock tells Peter to have Spider-Man meet him at 3:00 that afternoon. Now a resolute Peter regains his super powers and uses his webs to vault into Jonah’s office to steal his costume so quickly that no one sees him. Although Jonah had temporarily reversed his outspoken opinion that Spider-Man is a criminal, the theft of the suit convinces him to go back to his original opinion. That afternoon, Spider-Man meets Doc Ock on the roof of Harry’s building and enters into a battle of strength and wits that flows over onto an elevated train. During the fight, Doc Ock grabs the train’s controls, forcing it into high speed, but Spider-Man casts webs as anchors and uses all of his powers to stop the train before it crashes into the river. During the ordeal, in order to see more clearly, Peter throws off his Spider-Man mask, revealing his true identity to the terrified passengers, who are amazed that he is “just a kid.” After the passengers gently carry the exhausted Peter inside the train, two young boys return his mask and everyone promises that they will never tell anyone. After the mask is back in place, Doc Ock returns to the train and carries the still weakened Spider-Man to Harry’s penthouse. When Harry unmasks Spider-Man, he is stunned to see that his nemesis is his best friend. Harry does not kill Peter, who flees to Doc Ock’s lab. There Doc Ock refuses to release Mary Jane and starts his new experiment, using a large amount of Harry’s tridium. A battle ensues between Spider-Man and Doc Ock, during which he begins to think as Octavius again and wrestles with his conscience. Because Peter is still unmasked, Mary Jane sees that Spider-Man is Peter. As energy from the fusion experiment begins to unleash enormous power, Peter tells Mary Jane that he loves her, in case they die. Octavius now proclaims “I will not die like a monster” and forces the mechanical arms down under the water as the building collapses. After they safely escape, Mary Jane tells Peter “I think I always knew,” but he says they cannot be together because Spider-Man will always have enemies and she would be in danger. Back in Harry’s penthouse, he begins to hear the malevolent laugh of Green Goblin and hallucinates that his father is belittling him. To make it stop, Harry throws the knife with which he had intended to kill Spider-Man through a mirror and finds the hidden room where his father kept his Green Goblin paraphernalia. On Mary Jane and John’s wedding day, Mary Jane cannot go through with the ceremony and rushes to Peter’s apartment, still in her wedding dress. She says that she cannot live without him and asks “Isn’t it about time someone saved your life?” After they kiss, Peter responds to a siren by jumping out the window and flying through the streets on the powerful threads of his spider webs.