One year after defeating Doctor Octopus, Spider-Man 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 (comics) 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 with Harry crashing out and developing amnesia, wiping out his memory of Peter as Spider-Man. Meanwhile, police pursue escaped convict Flint Marko, who visits his wife and dying daughter before fleeing again, and falling into an experimental particle accelerator that fuses his DNA with the surrounding sand, transforming him into the Sandman (Marvel Comics), with powers to control sand and to deform at will.
After being bitten by a radioactive spider, ordinary high schooler Peter Parker assumes the identity of Spider-Man, a superhero with spider-like abilities who must save New York City from a never-ending string of villains.