Bride-to-be Susan Murphy (Reese Witherspoon) is hit by a meteorite on her wedding day to the time reporter Derek Dietl (Paul Rudd), causing them to absorb a substance called quantonium and grow into a giantess. Alerted to the fall of a meteorite in the first place then an Arctic base Susan's father, the military arrive and capture Susan, which is labeled as "Ginormica" and sent to a top-secret prison facility headed by General WR Monger (Kiefer Sutherland ), where he meets his fellow prisoners monsters: BOB (Seth Rogen), a brainless, indestructible gelatinous blob, Dr. Cockroach, Ph.D. (Hugh Laurie), a mad scientist with the head and abilities of a cockroach, the Ring missing (Will Arnett), an amphibian hybrid monkey-fish, and Insectosaurus, a caterpillar mass that is greater than Susan.
An alien named Gallaxhar (Rainn Wilson) detects the radiation from the Earth quantonium and distributes a gigantic robotic probe to find it. The U.S. president (Stephen Colbert) attempts to make first contact with the alien robot playing Axel F on a keyboard, but the attempt fails and the robot starts destroying everything in sight, impervious to any weapon. General Monger convinces the President to use the monsters to fight the robot instead. The monsters accept the mission with the promise of freedom, if they can. Arriving in San Francisco, Susan is chased by the robot across the city to the Golden Gate Bridge, where the monsters are able to defeat the robot.
Now free, Susan returns to her hometown and introduces her family to the show, but quickly rejected after innocently causing panic in the neighborhood. Derek, meanwhile, breaks up with Susan, claiming that he can not be married to a monster that would shadow his career. Initially devastated, Susan begins to realize that becoming a monster has improved her life, and fully embraces his new lifestyle. Suddenly, he is abducted by Gallaxhar, who apparently kills Insectosaurus when he tries to save her. On a spaceship Gallaxhar, Susan breaks loose and chases Gallaxhar down, only to enter into a machine that extracts the quantonium from his body, reducing her to her normal size. Gallaxhar proceeds to use the food quantonium for the cloning of a machine that reproduces in an army so that it can invade the Earth.
With help from General Monger, BOB, Dr. Cockroach, Missing Link and infiltrate Gallaxhar's spaceship, rescue Susan and hot wire core power the spacecraft, activating the self-destruct sequence. During their escape, Susan is cut off from their friends, who are trapped in the nucleus of power. They say to save herself, but Susan confronts Gallaxhar Instead, it tries to escape with the quantonium, and tries to force him releasing his friends. When Gallaxhar says he can not reverse the sequence, Susan takes up quantonium, returning herself to giant size and save his friends. The monsters jumping out of the spaceship explodes and is saved by General Monger on the back of the revived Insectosaurus, who turned into a butterfly.
The monsters receive a hero's welcome home. Derek tries to get back with Susan for the sake of an interview that could benefit his career. Instead, Susan rejects it by throwing it into the air, where it is caught, swallowed and spit out by BOB on camera. Monsters are then notified of a giant snail called Escargantua to attack near Paris and fly away to face the new threat.
