When a meteorite from outer space hits a young California woman named Susan Murphy (Reese Witherspoon) and turns her into a giant monster, she is taken to a secret government compound where she meets a ragtag group of monsters also rounded up over the years. As a last resort, under the guidance of General W.R. Monger (Kiefer Sutherland), on a desperate order from President Hathaway (Stephen Colbert), the motley crew of Monsters is called into action to combat the aliens and save the world from imminent destruction.