On the day of her big fat wedding to Derek, Susan is hit by a radioactive meteor. During the wedding she mutates in to a 50 foot giant, destroy the church. The military arrives investigating the meteor, but attacks Susan, sedating her with a giant syringe full of tranquilizer. She awakens in an a facility, were she is labeled as a monster named Ginormica, and becomes friends with four monsters named B.O.B., the The Missing Link, Dr. Cockroach, and Insectosaurus. An alien named Gallaxhar detects the quantonium radiation emanating from Earth and deploys a gigantic robotic probe to find it and extract it from its source, Susan. After a botched attempt by the President of the United States (Stephen Colbert) to make first contact with the robot, it begins destroying everything in sight, resisting all conventional military force used against it. 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 succeed. Arriving in San Francisco, Susan is chased by the robot across the city, and B.O.B gets stuck to the robots foot (who later is commanded to eat the rails dividing the roads in oder to help the people evacuate). Susan then lures the robot to the Golden Gate Bridge,where the Missing Link is knocked out, unable to fight. Insectosaurus then arrives and defeats the robot.
Now free, Susan returns to her hometown and introduces her family and friends to the monsters, who are quickly dejected after innocently causing a panicked ruckus in the neighborhood. Derek, meanwhile, breaks up with Susan, claiming that he can't be married to someone who could overshadow his career. Initially devastated, Susan realizes that becoming a monster has improved her life, and fully embraces her new friends and lifestyle. Suddenly, she is abducted by Gallaxhar, who apparently kills Insectosaurus when he tries to save her. On Gallaxhar's ship, Susan breaks loose and chases Gallaxhar down, only to enter a machine that extracts the quantonium from her body, shrinking her to her normal size. Gallaxhar proceeds to use the quantonium to power a machine which clones him into an army so he can invade Earth.
With assistance from General Monger, B.O.B., Dr. Cockroach, and the Missing Link infiltrate Gallaxhar's ship, rescue Susan, and hot-wire the ship's power core, activating the ship's self-destruct sequence. Susan, however, is cut off from her friends, who are trapped in the power core and tell her to save herself. Instead, Susan confronts Gallaxhar, who tries to escape with the quantonium, and attempts to force him into releasing her friends. When Gallaxhar says he cannot reverse the sequence, Susan takes the quantonium back and absorbs it, restoring her to her gargantuan size and allowing her to save her friends. The monsters leap out of the exploding ship and are rescued by General Monger on the back of the revived Insectosaurus, who had sealed his body in a cocoon and transformed into a giant butterfly.
The monsters receive a hero's welcome upon their return. Derek attempts to get back with Susan for the sake of interviewing her, which could benefit his career; instead, Susan rejects him and forces him to endure the humiliation of being thrown into the air and caught, swallowed and spit out by B.O.B. on camera. At that moment, the monsters are alerted to a monster (a giant snail) attack near Paris and fly off to combat the new menace.