In an opening cutscene, Spider-Man finds himself beset by his enemies from the movies: Green Goblin, Doctor Octopus, Sandman, and Venom. He gains help from New Goblin as he combats the villains. All six characters suddenly find themselves targeted by an enemy force and one-by-one, the villains begin disappearing. Meanwhile, Spider-Man is rescued by Nick Fury of S.H.I.E.L.D., who informs him that the meteor which brought the Venom symbiote to Earth had broken up in the Earth's atmosphere and five more pieces had landed in numerous locations across the globe. Fury sends Spider-Man to retrieve the shards of meteors. Spider-Man quickly finds that the villains who attacked him and several more of his foes, including Rhino and Scorpion, have been placed under mind control of a mysterious villain. The villain also creates and controls holographic/symbiote combination foot soldiers called P.H.A.N.T.O.M.s (short for Perpetual Holographic Avatar Nano-Tech Offensive Monsters). As Spider-Man fights his enemies one-by-one and rescues them from the mind control, they promise to aid him in finding the villain responsible. As Spider-Man progresses, he obtains more allies such as Black Cat, Iron Fist, Silver Sable, Prowler, Lizard (not portrayed as a villain), and Blade. He discovers that the evil genius is Mysterio (whom Venom refers to as "bubbleman"), who intends to use his army to take over the world, using each shard of the meteor to make them stronger. Spider-Man decides to temporarily don the Black Suit for the final battle. Ultimately, Spider-Man defeats him and turns the shards over to Fury, who decides to analyze them and refers to the study as "Project Carnage". Even though she does not appear in the game, Madame Web is mentioned when the computer says she is here for Nick's 4:00 meeting.