Arrows then appear, allowing Sketch to jump to another panel. In order to progress through the pages, Sketch often has to either successfully solve a puzzle or defeat all the enemies within that panel. Sketch must make his way through three episodes, each consisting of two pages. The game is a beat-'em-up played in the pages of a comic book. It is up to Sketch to stop Mortus's evil plans and find a way out of this comic world. Ignoring Sketch's protests, Alissa sends him on his mission, keeping in touch with instructions and hints via radio. Inside the comic book, Sketch meets General Alissa Cyan, who believes he is 'the chosen one' who came to save their post-apocalyptic world from the evil of Mortus and the alien invaders.

Because he does not possess any power in reality, Mortus sends Sketch into the world of his own comic, freely drawing in enemies attempting to kill him. In this instant, its main villain, a powerful mutant named Mortus, escapes the comic book's pages, desiring to kill Sketch so he can become flesh and blood and take over the real world. One night, while Sketch is working on Comix Zone during a thunderstorm, a lightning bolt strikes a panel of his comic. It 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. Sketch Turner, a 'starving artist' and freelance rock musician living in New York City, is working on his newest comic book, Comix Zone.

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