The city of Monstropolis in the monster world is powered by energy from the screams of human children. At the Monsters, Inc., factory, skilled monsters employed as "scarers" venture into the human world to scare children and harvest their screams, through doors that activate portals to children's bedroom closets. It is considered dangerous work, as human children are believed to be toxic. Energy production is falling because children are becoming less easily scared, and Henry J. Waternoose III, the company's CEO, is determined to find a solution to the problem. James P. "Sulley" Sullivan and his best friend, Michael "Mike" Wazowski, are the organization's top employees, but their chief rival, Randall Boggs, is close behind.
One evening after work, Sulley discovers that someone has left a door activated on the scare floor. He opens it and a small girl has entered the factory. After several failed attempts by Sulley to put her back, Randall sends the door back into the factory's door vault and Sulley conceals her and takes her out of the factory. He inadvertently interrupts Mike's date with his receptionist girlfriend, Celia Mae, at a Japanese sushi restaurant called Harryhausen's, and chaos erupts when the child is discovered. Sulley and Mike manage to escape with the child before the Child Detection Agency (CDA) is called by the Sushi Chief and quarantines the restaurant. They soon discover that she is not toxic after all; Sulley grows attached to her and calls her "Boo", while Mike is just anxious to be rid of her.