Scientist Richard Parker records a video message to explain his disappearance. Later, he and his wife, Mary, are aboard a private jet h...
In the present, Richard and Mary's son Peter continues to fight crime as Spider-Man. He pursues and apprehends Aleksei Sytsevich, who attempted to steal a truck containing plutonium vials. During the chase, Spider-Man rescues OsCorp Industries employee Max Dillon. While speaking by phone with Gwen Stacy, Peter sees a vision of her deceased father, police captain George Stacy, reminding him to leave Gwen out of his affairs as Spider-Man. After their high school graduation, Peter meets with Gwen at a restaurant outside, but insists he needs to keep his vow to her father by staying away from her; upset, Gwen ends their relationship.
Peter's childhood friend Harry Osborn returns to Manhattan to see his terminally ill father Norman, CEO of OsCorp. Norman explains his illness is hereditary, and Harry is at the age where it first develops. Norman gives Harry a small device he claims contains his life's work. The next day, Norman dies and Harry is appointed the new OsCorp CEO. He accuses the OsCorp board of trying to wrest control from the Osborns, as they have been privy to Norman's secret biogenetic projects for foreign military powers.
Thinking they have become "best friends", Max idolizes Spider-Man. While tending to some maintenance in an OsCorp laboratory, he gets electrocuted and falls into a tank of genetically modified electric eels. They attack him, mutating him into a living electric generator. Meanwhile, Peter attempts to maintain a friendship with Gwen, but she reveals that an opportunity for a scholarship at Oxford University meant that she may move to England. Before they can discuss it, Max wanders into Times Square and accidentally causes a blackout. Spider-Man attempts to calm him down, but the police fire at Max, and Spider-Man's resulting rescue of the endangered citizens draws media attention away from Max, making him lose his temper and attack. Spider-Man eventually stops him, and Max is taken to Ravencroft Institute.
Harry's illness begins to show, and he deduces that Spider-Man's blood may save him. He asks Peter for help finding Spider-Man. Peter attempts to dissuade him, unsure of what effects the transfusion would have, and although he does come to Harry as Spider-Man, he still refuses; Harry develops an intense hatred towards Spider-Man. The OsCorp board members frame Harry for covering up Max's accident, and remove him as CEO. Harry's assistant informs him of equipment that could help him, so he works with Max to get him back inside the OsCorp building. There, he finds a suit of armor, other equipment made by Norman, and venom from the genetically altered spiders. The venom accelerates his illness and transforms him into a goblin-like creature. The suit detects Harry's condition, and a built-in emergency protocol restores his health.
Peter uses information left by his father to locate the video message in a hidden lab. Richard explains that he had to leave because he refused to cooperate with Norman's biogenetic weaponization plans. Peter receives a voicemail from Gwen, telling him she received the scholarship at Oxford and was leaving for England earlier than expected. He manages to catch her, professes his love for her, and decides to go to England. When Max causes another blackout, Peter and Gwen go to confront him. They restore power and overload Max's body, killing him in the process. Harry arrives equipped with Norman's armor and weaponry; upon seeing Gwen, Harry deduces Spider-Man's true identity and kidnaps her. Spider-Man subdues Harry, but despite his attempts to save Gwen, she dies. A distraught Peter gives up being Spider-Man and he spends several days throughout the year at Gwen's grave.
Over the next five months, Harry is healed from his transformation at Ravencroft. His associate, Gustav Fiers (the "man in the shadows" from the first film), visits Harry and breaks Sytsevich out of prison. Equipped with a mechanical suit of armor, Sytsevich calls himself the Rhino and rampages through the streets. Peter, inspired by Gwen's graduation speech, returns to battle him as Spider-Man.
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