Sketch Turner, "starving artist" and freelance rock musician, is working on his newest comic book, named "Comix Zone." Comix Zone is the story of the New World Empire's attempt to defend Earth from an invasion of alien renegades, with inspiration coming from Sketch's (oddly vivid) dreams and nightmares. One night, while Sketch is working on Comix Zone during a storm, a massive lightning bolt strikes outside his apartment, somehow affecting the comic book too. In this instant, the villain of Comix Zone - a powerful mutant named Mortus - manages to escape the comic book's pages, and hurl the stunned Sketch into the world of Comix Zone. Inside the comic book, Sketch meets General Alissa Cyan, who believes he is a superhero ("the chosen one") who has come to save their post-apocalyptic world from the evil of Mortus and the alien invaders. Ignoring Sketch's protests, Alissa sends him on his mission, keeping in touch with instructions and hints via radio. Now that Mortus has a physical presence outside of Comix Zone, he is free to change the world as he wishes, simply by drawing in enemies for Sketch to face - or in one instance burn up part of a page.
Sketch is capable of tearing shreds out of the backdrop and folding them into paper planes to throw at enemies as a weapon. Because this paper world is also part of everything within Comix Zone (as they are drawn on it), this action takes a significant slice off the player's health bar. Certain combos will send enemies hurtling, and if a fragile border between frames is in the way the enemy crashes through it, tearing it to shreds. When confronted with an unbreakable frame barrier, the hero merely swings himself out of the frame, over the top of the border, and back down into the next scene. Sketch's pet rat Roadkill (whom he saved from certain doom in a garbage truck) is also capable of operating switches and discovering items hidden in panels, making him useful in helping Sketch's progress through Mortus' traps.