The game is set in 1969, 12 years after the original. The game begins with a KGB slide show meeting showing that the main character from Destroy All Humans!, Cryptosporidium-137, is now deceased for unknown reasons. His clone, Cryptosporidium-138 (Crypto for short), made of more pure furon DNA, is now taking his place and continuing to pose as the United States President. KGB intelligence reveals that Crypto-138 is the first and only Furon to have genitalia, referred to only as "The Package". Seeing the furons as a threat to the Soviet Union, the KGB destroy the furon mothership with a nuclear missile.
Destroy All Humans! 2 has a co-op multiplayer mode, so the player can play through the story mode, free roam together and minigames, such as PK Tennis and Duel, with a friend.