A woman named Susan Murphy is struck by a meteorite on her wedding day, causing her to grow to an enormous size and gain immense strength. The military captures her and sends her to a secret government facility where she meets other monsters: Dr. Cockroach, a scientist turned cockroach; B.O.B., a gelatinous blob; The Missing Link, a fish-ape hybrid; and Insectosaurus, a colossal insect. They have been held for years to keep them hidden from society. The monsters are called into action when an alien named Gallaxhar plots to invade Earth, hoping to use a mysterious substance found within Susan to power his plans.

President Hathaway authorizes the monsters to battle Gallaxhar's forces, promising them freedom in return. The monsters face various challenges as they confront Gallaxhar's technologically advanced robot and alien army. Along the way, Susan learns to embrace her new identity and the unique strengths of her fellow monsters. They work together using their individual abilities to combat the alien threat.