The intermission scenes between each level feature Spider-Man trading catchy barbs with a supervillain on a cell phone or walkie-talkie to find out where he should go next.

Spider-Man's most dangerous supervillains have discovered his secret identity, Peter Parker, and kidnapped his wife, Mary Jane.

The action game takes the player through various city locations, battling an assortment of minor thugs, animals, and a supervillain (Mysterio, Hobgoblin, Scorpion, Rhino, Dr. Octopus, Venom) at the end of each level who, through intermission scenes, will taunt Spider-Man as to the whereabouts of his wife.

The game's story follows a collection of supervillains (the Hobgoblin, Lizard, Graviton, Carnage, and Mysterio) who have framed Spider-Man for a bank robbery.

The game is based loosely on the comic book storyline of the same name, with Spider-Man being attacked by an assortment of high-tech robot Spider-Slayers.