Big Willy Unleashed takes place after Destroy All Humans! 2 and before Path of the Furon. This game is set during year 1975 (6 years after these events of Destroy All Humans! 2). Cryptosporidium 138 and his mentor, Orthopox 13, attempt to support the popularity of Big Willy, a fast food restaurant Orthopox owns. Pox reveals that the Big Willy food franchise is actually a scheme to dispose of the human bodies Crypto leaves lying around.