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.
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.