New York City is infected! Dr. Curt Connors - aka The Lizard - is in a mental hospital after the events of the movie. When his work at Oscorp with different cross-species comes to light and they break free, infecting others with an illness through mere touch, new Oscorp science head Allistair Smythe invents robots to kill the cross-species and the infected New Yorkers. Spidey must team up with Conners and Gwen Stacey to stop a horde of genetic creatures and save the city!

Using the game's new Web Rush mechanic, players can pull off a vast array of moves never before possible. With a story that takes players through many areas all over (and under) Manhattan, fans will feel what it's truly like to be a Super Hero, as they experience the cinematic adrenaline rush of web-swinging through the city and fighting crime using Spider-Man's spectacular acrobatic moves and attacks.