Crypto is back yet again for the third game in the series. The game takes place sometime in the 1970s, a decade after the last installment. Crypto and his mentor Orthopox attempt to exploit the popularity of Big Willy, a fast food restaurant owned by Pox. His secret recipe is actually human meat, served from the dead bodies that were left behind after Crypto got their brain stems. A kidnapped heiress by the name of Patty Wurst has discovered the secret recipe of the restaurant, and Crypto and Pox set on an adventure to stop her before she can expose them.

The game is set in the 1970s. There is now a third way to unleash fury besides on foot and in a UFO aircraft: a Big Willy Machine! There are five different places to explore: Harbor City, Fairfield, Vietmahl, Fantasy Island, and Antarctica. There are futuristic weapons and unique mental abilities. It wouldn't be a Destroy all Humans! game without humor and over the top, non-stop action. Popular abilities such as Psychokinesis and Body Snatch return as well as Crypto's Zap-O-Matic and Disintegrator Ray. New abilites include the saucer's Electro-Cone and Quantum Deconstructor. Crypto also has new guns, including the Ball Lightning and a zombie gun that turns its victims into zombies.