Bride-to-be Susan Murphy (Reese Witherspoon) is getting ready to marry weather reporter Derek Dietl (Paul Rudd) and is excited about their honeymoon in Paris. Her supportive parents, Carl (Jeffrey Tambor) and Wendy (Julie White), cheer her on as she daydreams about a future filled with adventure, believing that Derek will eventually become a foreign correspondent allowing them to explore the world together. However, mere moments before the ceremony, Derek reveals he has a job interview in Fresno instead of heading to Paris, testing Susan's commitment to his career.
In a shocking turn of events, just before the wedding, a meteorite from a shattered planet crashes in Modesto, California, where the ceremony takes place. Instead of the expected doom, it exposes Susan to a mysterious substance called Quantonium. While she initially seems unharmed, during the ceremony, her body undergoes a shocking transformation—her hair turns white, her skin glows green, and she dramatically grows to over 50 feet tall. This unforeseen spectacle sends wedding guests fleeing in terror as she bursts through the chapel roof.
The military is quickly alerted to the meteorite's impact and, after assessing the situation, they capture Susan, now codenamed "Ginormica." She is taken to a classified facility overseen by General W.R. Monger (Kiefer Sutherland), where she meets a group of fellow monsters: B.O.B. (Benzoate Ostylezene Bicarbonate) (Seth Rogen](/actor/seth-rogen)), a mindless, indestructible mass of blue goo; Dr. Cockroach, PhD (Hugh Laurie), who is now a half-human, half-cockroach hybrid due to a scientific mishap; the Missing Link (Will Arnett), an ancient fish-ape hybrid; and Insectosaurus, a colossally-sized bug transformed by nuclear exposure.
As the first new monster and the only female in the group, Ginormica learns that this facility was established in the 1950s to safeguard monstrous beings from public knowledge. Monger informs her that she will not be allowed to contact her family or Derek, who will remain oblivious to her situation.
Meanwhile, on his spaceship, an alien overlord named Gallaxhar (Rainn Wilson) discovers the presence of Quantonium on Earth and sends a massive robotic probe to seize it. The President of the United States (Stephen Colbert) attempts to establish communication with the robot, but his efforts backfire as the machine begins a path of destruction towards San Francisco, impervious to military attacks.
In a surprising strategy, General Monger proposes that the President unleash his monsters to confront the robot. The monsters accept the mission on the promise of freedom should they succeed. As the showdown occurs, the monsters cleverly utilize parts of the Golden Gate Bridge to defeat the robot while the government honors their agreement by granting them their freedom.
Once back in Modesto, Susan introduces her monstrous friends to her family, but the chaos they inadvertently cause leads to rejection. Heartbroken after Derek dismisses her due to her new appearance, Susan resolves to embrace her monster identity, vowing never to revert to her previous self.
However, Gallaxhar abducts her, leading to a perilous encounter aboard his spaceship where he attempts to extract the Quantonium from her. After a series of confrontations, Susan manages to escape with the help of her friends, culminating in a thrilling confrontation that sees her regain her giant form. The group successfully manages to escape just as the ship self-destructs, eliminating Gallaxhar and his clone army.
Upon returning triumphantly to Modesto, the reunion is marred by Derek's re-entrance, who tries to rekindle their relationship, but Susan turns him down, humiliating him during a live interview. As they celebrate with newfound camaraderie, Monger informs them of an impending threat— a monstrous snail named "Escargantua" is making its way to Paris, setting the stage for their next thrilling adventure.
