Synopsis:Richard Parker records a video message to explain his disappearance. Later, he and his wife, Mary, are aboard a private jet hijacked by a man sent to assassinate Richard. With the pilot dead, the plane crashes.
In the present, Richard'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 father, police captain George Stacy, reminding him to leave Gwen out of it. Afterward, Peter meets with Gwen at their high school graduation ceremony, but insists he needs to keep his vow to her father and 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, only to become corrupt among the Oscorp board, causing them to plan on firing him.
Assuming they are now friends, Max becomes interested in Spider-Man. While tending to some maintenance in an Oscorp laboratory, he loses his balance and falls into a tank of electric eels being used for experiments. The electricity mutates him into a living electric generator. Meanwhile, Peter tries to maintain a friendship with Gwen, but she reveals she is moving to England for school. 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, making him lose his temper and attack. Spider-Man eventually stops him, and Max is taken to Ravencroft Institute.
The first symptoms of Harry's illness show, and he uses the device Norman gave him to deduce that Spider-Man's blood could help save him. He asks Peter, who has been sending photos of Spider-Man to The Daily Bugle, for help finding Spider-Man. Peter refuses, unsure of what effects the transfusion would have. The Oscorp board-members frame Harry for covering up Max's accident, and remove him as CEO. Harry's assistant, Felicia Hardy, informs him of equipment that could help him, so he makes a deal with Max (now calling himself "Electro") to get him back inside the Oscorp building. There he finds a suit of armor and other equipment made by Norman, as well as venom from the now-destroyed genetically altered spiders. Instead of curing him, they transform him into a hideous, goblin-like creature.
Peter uses information left by his father to locate the video message. In it, Richard explains he had to leave New York because he was unwilling to cooperate with Norman Osborn's plans to use what they had created for biological weapons. Peter then receives a voicemail message from Gwen, telling him she was offered the scholarship in England and is heading to the airport earlier than expected. He manages to catch her and professes his love for her, and they agree to go to England together. Electro causes another blackout, and Peter heads off to fight him. Gwen follows, and they kill Electro in an explosion caused by overloading his electricity supply. Afterward, the transformed Harry arrives equipped with Norman's armor and weaponry; upon seeing Gwen, Harry deduces Spider-Man's true identity and, wanting revenge for being refused the blood transfusion, kidnaps her. He fights Spider-Man at the top of a clock tower, and though Spider-Man subdues Harry, Gwen dies.
Months later, Peter has given up being Spider-Man and spends every day at Gwen's grave. Harry is healing from his transformations, and his associate (the "man in the shadows" from the first film) breaks Alexsei Sytsevich out of prison, gives him the code name "Rhino" and equips him with a mechanical suit of armor. Rhino rampages through the streets, and a recording of Gwen's graduation speech inspires Peter to return as Spider-Man and confront him.