A few minutes before her wedding to Derek Dietl (Paul Rudd
), a TV weatherman, Susan Murphy (Reese Witherspoon
) is hit by a meteorite. The meteorite is infused with quantonium, a rare and powerful element that causes her to grow -- just as she begins to recite her vows -- to an enormous size. Targeted by the government as a monster, Susan is captured and imprisoned at a secret facility where other such oddities are being held, including Dr. Cockroach (Hugh Laurie
), a mad scientist who accidentally transformed himself into a roach-human hybrid; B.O.B. (Seth Rogen
), a gelatinous, brainless, but talkative mass brought to life in an experiment gone wrong; the Missing Link (Will Arnett
), a Creature-from-the-Black-Lagoon-like lizard man; and the skyscraper-sized mutant larva Insectosaurus. Their jailer is General W.R. Monger (Kiefer Sutherland
When deranged alien overlord Gallaxhar (Rainn Wilson
) comes to Earth to obtain the precious quantonium and conquer the world, U.S. President Hathaway (Stephen Colbert
) offers the monsters their freedom in exchange for defeating the evil mastermind. They're turned loose in San Francisco and Gallaxhar's giant robot quickly fixates on Susan. It corners her on the Golden Gate Bridge. Thanks largely to Susan's amazing strength and determination to keep anyone from being hurt, the monsters are able to destroy the robot.
Susan takes her monster friends to visit her parents, but they frighten all the neighbors at the backyard barbecue. Derek doesn't attend. When Susan seeks him out, he breaks up with her; it's apparent that all he cares about is his career, and he doesn't think a 50-foot wife will help him move into larger markets. Susan quickly realizes that she's better off without Derek, and that she likes her new self, her new abilities, and her new friends. She rejoins the other monsters only to be snatched up into Gallaxhar's spaceship. Insectosaurus is felled when it tries to help her.
Despite Susan's brief escape and determined resistance, Gallaxhar extracts the quantonium from Susan's body and she returns to her original dimensions. The quantonium is key to Gallaxhar's evil plan to take over the world: it enables him to create legions of clones, who march around in formation saying "Hail Gallaxhar!" Meanwhile, the surviving monsters have snuck aboard to help Susan. They send the ship into self-destruct mode. Only Susan makes it out of the engine room before the doors close; Dr. Cockroach, B.O.B., and the Missing Link, stuck inside, insist that she escape without them. But Susan is made of tougher stuff than that; she goes back to Gallaxhar and tries to make him abort the self-destruct and release her friends. When Gallaxhar tries to escape, Susan regains possession of the quantonium and becomes a giant again. After she frees her friends, they're all rescued from the self-destructing ship by General Monger and Insectosaurus, who wasn't dead after all -- just busy metamorphosing into a moth the size of a 747.
Before Susan and the monster squad are called away to save another day, there's a big celebration during which Derek tries to interview Susan. She spurns him and allows B.O.B. to swallow him and spit him out, a career-killing moment that Susan makes sure will be caught on camera.
Susan Murphy (Reese Witherspoon) is hit by a meteorite on the day of her wedding to weatherman Derek Dietl (Paul Rudd), absorbing a substance called quantonium and growing into a giant. Alerted to the meteorite crash, the military arrive and capture Susan. She is labeled a monster, renamed "Ginormica" by the government, and sent to a top-secret prison facility headed by General W.R. Monger (Kiefer Sutherland) and containing other monsters: B.O.B. (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 Missing Link (Will Arnett), an amphibious fish-ape hybrid; and Insectosaurus, a colossal grub that is even larger than Susan. The monsters are forbidden to have any contact with the outside world; while the other monsters have been living contentedly with this lifestyle for the past 50 years, Susan feels incredibly isolated and wishes to return to her old life.
An alien named Gallaxhar (Rainn Wilson) 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 to the Golden Gate Bridge, where the monsters are able to defeat the robot, Susan and Insectosaurus keeping it occupied while Dr. Cockroach sabotages it from inside and B.O.B. clears a path for the cars to evacuate (The Missing Link having been knocked out during the fight).
Now free, Susan returns to her hometown and introduces her family and friends to the monsters, who are quickly rejected 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 spaceship, 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 spaceship, rescue Susan, and hot-wire the spaceship's power core, activating the spaceship's self-destruct sequence. However, during their escape attempt, Susan 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 spaceship 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 attack near Paris and fly off to combat the new menace. [D-Man2010]