An alien named Gallaxhar found out that the quantonium radiation was on Earth so it deploys a gigantic robotic probe to find it and extract it from its source, Susan. Then the president of the United States try to make first contact with the robot, but failed. Then it begins destroying everything in sight. The military forces had given everything but failed so 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.
Now free, Susan returns to her hometown and introduces her family and friends to the monsters, who are quickly rejected by the neighborhood. Derek breaks up with Susan, because she would overshadow his career. Feeling devastated, Susan realizes that becoming a monster has improved her life, and fully embraces her new friends and lifestyle. Then she was abducted by Gallaxhar, so it can abstract the quantonium. Gallaxhar succeed and Susan shrinks to normal size. Gallaxhar proceeds to use the quantonium to power a machine which clones him into an army so he can invade Earth. With the help of the other monsters, Susan able to infiltrate Gallaxhar's ship and activating the ship's self-destruct sequence. In the end, she and her monster friends able to destroy Gallaxhar from destroying the Earth.