When California girl Susan Murphy is unexpectedly clobbered by a meteor full of outer space gunk, she mysteriously grows to 49 feet, 11 inches tall and is instantly labeled a "monster" named Ginormica. The military jumps into action, and she is captured and held in a secret government compound. The world learns that the military has been quietly rounding up other monsters over the years. This ragtag group consists of the brilliant but insect-headed Dr. Cockroach, Ph.D.; the macho half-ape, half-fish The Missing Link; the gelatinous and indestructible B.O.B.; and the 350-foot grub called Insectosaurus. Their confinement time is cut short however, when a mysterious alien robot lands on Earth and begins storming the country.

As a last resort, under the guidance of General W.R. Monger (on a desperate order from The President), the motley crew of Monsters is called into action to combat the aliens and save the world from imminent destruction.