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6-year-old monster Michael "Mike" Wazowski (Billy Crystal) was on a school field trip to Monsters Inc., a scaring company. As a kid, nobody wanted to be a buddy with Mike, and he has to go through the field trip with the teacher Karen (Bonnie Hunt) as his partner. The kids from class are taken to the scare floor. At Monsters Inc., the class meets "Frightening" Frank McCay (John Krasinski), an employee of the company who works as a "Scarer", entering the human world to scare children at night and harvesting their screams as energy to power the monster world. Frank says that he studied at Monster's University, which he considers to be the best scare school.

As Frank prepares to enter a door to the human world, the children notice that Mike has slipped unnoticed to Frank's door, which he then enters before anyone can stop him. Mike watches Frank's scare performance, then follows him back through the door to the monster world. Frank scolds Mike but is impressed with his ability to have sneaked quietly in and out of the room and gives him his Monsters University hat as a souvenir. The teacher reprimands him as well, but Mike is happy and inspired to be a Scarer when he grows up.

Approximately thirteen years later, Mike is a scare major and is starting his first day at the prestigious Monsters University. Everything in Mike's life has led to this moment and Mike cannot wait to get started. On the official tour, Mike learns that the University has a department where students learn to design and build the doors to the human world. But the crown jewel of MU is the scaring school. MU's Greek Council sponsors the annual Scare Games.

On his first day, Mike befriends his roommate, the nerdy and shy Randall "Randy" Boggs (Steve Buscemi), who desires to be popular and has difficulty controlling his camouflage power. Mike believes that he and Randy will be lifelong best friends. During the first class of the scare program, as Mike is answering a question, he is interrupted by another scare student, an arrogant large blue monster named James P. "Sulley" Sullivan (John Goodman) the son of a famous Scarer. Mike is a diligent and hardworking student, while Mike comes to class unprepared and doesn't take the classes seriously yet still earns credits from the professors due to his pedigree.

The entire class is also informed by Dean Hardscrabble (Helen Mirren), the chair of the Scarer program and president at Monsters University, that they must pass their final exam of the semester in order to continue in the program. Dean Hardscrabble is the holder of the all-time scare record.

While Mike is studying one night, Sulley inadvertently barges into his room in order to hide the pig mascot of a rival college. While the two bicker, the mascot steals Mike's treasured MU hat and escapes. Mike and Sulley chase the pig outside and struggle to capture it, but when Mike finally manages to do so, Sulley gets the credit, and is invited to join Roar Omega Roar, the elite fraternity on campus. Mike wishes to join, but is denied for not being scary enough, magnifying the rivalry between the two. Johnny J. Worthington III (Nathan Fillion) is the president of Roar Omega Roar fraternity.

Mike studies hard and repeatedly answers questions in class correctly, while the privileged Sulley, convinced all he needs is his natural scaring ability, begins to falter. An intense rivalry forms between Mike and Sulley throughout the semester, seeing each other as the antithesis of their views on success. On exam day, the duo's rivalry gets out of control. The students are asked to perform real scares in the scare simulator under different scenarios. They engage in a showmanship prior to their test and inadvertently destroy Hardscrabble's prized scream canister. Hardscrabble drops them from the program, Sulley for a lack of technical knowledge and rushing and Mike for not being physically "scary".

This prompts Roar Omega Roar to kick Sulley out of the fraternity. Unhappy in his boring new major of scream-can design, Mike decides to enter the Scare Games, an extracurricular competition involving a series of physical challenges that tests a monster's scaring ability. As the participants must be members of a fraternity or sorority, Mike joins Oozma Kappa, a small fraternity of misfit monsters.

The fraternity includes Don Carlton (Joel Murray) a middle-aged returning student and the founding member and president of Oozma Kappa fraternity, Terri (Sean P. Hayes) and Terry Perry (Dave Foley) who share each other's body, Art (Charlie Day), Scott "Squishy" Squibbles (Peter Sohn) and others.

Mike tries to enter Oozma Kappa (OK) into the scare games but is told he needs one more member. Sulley, seeing the competition as his ticket back into the scare program, offers to join, which Mike eventually reluctantly accepts. The sign-ups were closing and absolutely nobody else wanted to join the Oozma Kappa. In the process of joining, Mike makes a deal with Dean Hardscrabble, the founder of the games, to re-admit their entire team to the scaring program if they win, whereas if they lose, Mike must leave Monsters University. Sulley expects to carry the team himself, but Mike believes that with enough training, the team can succeed. Meanwhile, Randy becomes a member of Roar Omega Roar and breaks off his friendship with Mike. The team is in a sorry state and their fraternity house is actually Scott's mother's home. Mike and Sulley are made to share a room.

The last-placing team in each round of the Games is eliminated from the competition. The first challenge is to go through a room of toxic glow urchins as fast as possible, with the slowest team being eliminated. Mike and Sulley forget that this is a team event and race ahead of the rest of the team, who struggle to cross the course. Initially, OK places last in the first round but are saved from elimination when another team is disqualified for cheating (as they used an illegal protective gel) and barely passes the second round.

They then attend a party at Roar Omega Roar house where initially the other competitors appear to accept them, but the fraternity pranks and humiliates them instead. The group is discouraged as they are now the laughingstock of the entire campus. The team becomes discouraged, so Mike takes them to Monsters Inc., where they sneak in and watch the Scarers using their differences as advantages. After being chased off by security, the rejuvenated team begins to work together under Mike's coaching and passes the next two challenges right behind Roar Omega Roar.

After that, Oozma Kappa uses their wits to advance all the way to the final round against Roar Omega Roar. Even having advanced so far, Sulley does not believe that Mike can be a true Scarer because of his lack of natural ability. In the final challenge, OK and Roar Omega Roar face off in a simulator in one-on-one matches, each trying to frighten a dummy child. After the team surprisingly wins the final round, Mike discovers that Sulley has manipulated the equipment so that Mike would register a perfect score. Mike is heartbroken and wants to prove to everyone that he is capable of becoming a Scarer.

He breaks into the door lab and uses a newly-crafted door to enter the human world, but his plan goes wrong when it turns out the door leads to a summer camp and he completely fails to scare the children. The rest of OK discard the trophy in disappointment as Sulley, ashamed of what he had done, then admits his guilt to Hardscrabble, just as she is notified of the break-in.

Realizing what happened, Sulley enters the door to look for Mike. After finding Mike and reconciling, the pair, now being pursued by human adults, attempt to return, but Dean Hardscrabble has deactivated the door until the Child Detection Agency arrives, trapping them in the human world. Mike realizes that the only way to get back into the monster world is to generate enough scream energy to power the door from their side. Working together, Sulley and Mike scare the investigating adults, generating an overwhelming amount of scream energy and allowing them to return to the lab.

Their actions lead to their expulsion from the university, but the other members of Oozma Kappa have been accepted into the scare program the next semester as Hardscrabble was impressed with their performance in the games. They share goodbyes and as Sulley and Mike leave, Hardscrabble admits they surprised her and changed her outlook on a monster's potential as Scarers and expresses her hope that they can continue to surprise others moving forward. The duo goes to work for Monsters Inc. in the mail-room and over the years work their way up through the ranks in the company until Sulley becomes a Scarer, with Mike as his coach/scare assistant.

The yellow slug-like monster, who was seen earlier, finally arrives at the classroom but discovers that the school year is over and runs back which he spends his entire vacation on.