Players choose one of the three original monsters to rescue. The player then uses the characters in the part of the world where the rescue is held. They work as a collective to break buildings, eat people, and destroy cars and this creates competition among players. When a player (literally) unlocks George, Lizzie, or Ralph, then they become playable characters. Once all the monsters are rescued, aliens begin to invade the earth, leaving the monsters the only ones who can save the planet they just helped partially destroy. After fending off the invasion on Earth, the monsters rescue Myukus (a cyclops-like alien) from Area 51 before chasing the aliens through space, destroying the aliens' bases throughout the Solar System and eventually rampaging through their homeworld.

George, Lizzie, and Ralph have been captured and confined for the world to see. George is held captive in New York City, Lizzie is imprisoned in Tokyo, and Ralph is stored in London (references to King Kong, Godzilla, and Werewolf of London (or An American Werewolf in London, respectively). However, Scumlabs, who has just rebuilt their facilities in Salt Lake City, causes another accident that results in three new monsters: Boris, a rhinoceros, Curtis, a mouse, and Ruby, a lobster.