Spider-Man defeats many crooks and escaping prisoners before the Rhino busts out of the prison. Spider-Man follows it to the New York Maximum Security Prison where a large group of thugs are causing a riot. Spider-Man dispatches the crooks quickly, but the van drives away on automatic. The storyline for the game starts off with a cutscene of a gray van being chased down by the police before it crashes, and out comes two crooks. Black Cat then leads Spider-Man to an illegal weapons trade, where she tries to convince him to permanently become Spider-Man, but he rejects the idea, saying that he cannot stop being either Spider-Man or who he really is. Jonah Jameson uses these photos to make it appear that Spider-Man is in league with Mysterio. Peter takes a few photos of Beck as Mysterio, and J. Mysterio tells Spider-Man that he trifles with his power once again, Mysterio tells him that Peter will face his doom today, and he hits him as Mysterio's helmet drops reveals himself to be Quentin Beck. Shocker is apprehended in a warehouse after attempting to use an experimental propulsion system to enhance his powers, while Mysterio is knocked out with one punch from Spider-Man while trying to rob a Speedy Mart. Spider-Man eventually teams up with Black Cat, who leads him to the Shocker, who escaped during Beck's initial competition with Spider-Man. Both of these attacks are thwarted by Spider-Man's efforts, with no casualties.
The embarrassment causes Beck to assume the identity of Mysterio, attacking journalists attending his press conference, and commands his "UFOs" to "invade" the Statue of Liberty. Consequently, Beck tries to kill Spider-Man, but is thwarted.
In the time following, special effects artist Quentin Beck tries to prove that Spider-Man is a fraud by challenging Peter in a series of "games". Octopus, kidnaps Aunt May, but she is saved by Spider-Man.