Bride-to-be Susan Murphy is struck by a meteorite right before her wedding to weatherman Derek Dietl. The meteorite exposes her to the substance quantonium. As the wedding is in progress, she rapidly grows, tearing most of her dress and smashing the church; as a side-effect, her hair turns white. Alerted to the meteorite, the military arrives and captures Susan, who is given the code name "Ginormica" and sent to a top-secret secure facility headed by General W.R. Monger. There she meets her fellow monster inmates: B.O.B., a brainless, indestructible gelatinous blob; Dr. Cockroach, PhD, a mad scientist with the head and abilities of a cockroach; the Missing Link, an amphibious fish-ape hybrid; and Insectosaurus, a massive grub that is even larger than Susan.
Far out in space, an evil alien named Gallaxhar detects quantonium radiation on Earth and deploys a gigantic robot probe to find it. After the robot lands, the President of the United States attempts to make first contact with it but fails, and the impervious robot begins destroying everything in sight. General Monger convinces the President to use his monsters to fight the robot. The monsters are promised their freedom, if they succeed, and accept the mission. Arriving in San Francisco, Susan is chased by the robot over the Golden Gate Bridge, where the monsters defeat it.
Now free, Susan returns home and introduces her family to the monsters. They are quickly rejected, though, after innocently causing a neighborhood panic. Derek breaks up with Susan, claiming that he cannot be married to someone who would overshadow his career. At first devastated, Susan realizes that becoming a monster is an improvement on her life, and fully embraces her new role. Suddenly, she is abducted by Gallaxhar, who appears to kill Insectosaurus in the process. On Gallaxhar's spaceship, Susan escapes and chases Gallaxhar down, only to be lured into a machine that extracts the quantonium from her body, which shrinks her back down to her normal size. Gallaxhar then uses the extracted quantonium to power a machine that clones himself into an army to invade the Earth.
With General Monger's help, B.O.B., Dr. Cockroach and the Missing Link infiltrate Gallaxhar's spaceship, rescue Susan, and hot-wire the spaceship's power core, activating the self-destruct sequence. During their escape, Susan is cut off from her friends, who are trapped in the power core. They tell her to save herself, but Susan instead finds Gallaxhar, who is trying to escape with the quantonium. She tries to force him into releasing her friends, but when he admits he cannot reverse the sequence, Susan instead takes the quantonium, restoring herself to huge size and saving her friends. The monsters leap out of the exploding spaceship and are rescued by General Monger on the back of the transformed Insectosaurus, who has metamorphed into a Butterflysaurus, while Gallaxhar is trapped, when his escape pod deactivates, and dies in the explosion.
The monsters receive a hero's welcome home. Derek tries to get back with Susan, since now it would benefit his career, but Susan rejects and humiliates him by throwing him in the air to be caught, swallowed, and spat out by B.O.B. on camera. The monsters are then alerted to a huge snail named Escargantua attacking Paris and they fly off to face the new menace.