Upon returning home early from a business trip, attorney Mitch Martin walks in on his girlfriend Heidi watching porn. Initially relieved, it turns out she has planned an orgy. Learning she regularly partakes in them, he decides to break up with her. A few days later, Mitch encounters his high school crush, Nicole, at the wedding of his friend Frank and makes an awkward impression. Later, he moves into a house located near the campus of the fictional Harrison University in Upstate New York.
Mitch's other friend Bernard throws a housewarming party at Mitch's house, dubbed Mitch-A-Palooza, which is a huge success. Frank gets drunk and is seen streaking by his wife Marissa and her friends, putting a strain on their new marriage. The following morning, the trio run into an old acquaintance whom they used to ridicule at school: Gordon Pritchard, who is now the college dean. He informs them they must vacate the house because it's exclusively for campus housing. Bernard proposes starting a fraternity that is open to anyone to meet the housing criteria. The new fraternity carries out several hazing events throughout campus, attracting the attention of Pritchard and other faculty members.
At a birthday party for one of Bernard's children, Nicole brings her boyfriend Mark and Mitch later walks in on him in the bathroom as he hooks up with another girl. While initially discreet, Mitch is forced to recount the incident to Nicole when Mark lies that the girl was with Mitch instead of himself. Later, the oldest fraternity member, Blue, dies of a heart attack during a "KY lube wrestling" match with two college girls at his birthday celebration. At Blue's funeral, Marissa asks Frank for a divorce.
Plotting revenge against the group, Pritchard asks the student council president, Megan, to revoke the fraternity's charter. Megan, who met her boyfriend at one of their parties, initially remains loyal to the fraternity until the dean bribes her with promises to help her get into Columbia Law School. By video, he claims that the group is violating university policies, subjecting the students in the non-sanctioned fraternity to expulsion.
Mitch learns that the group has the right to bypass the Pritchard's ruling if all of their members complete various activities to prove their legitimacy. Frank is able to defeat James Carville in a debate session. Next, the fraternity successfully navigates its way through an academic exam largely due to the assistance of two of Mitch's co-workers, who help everyone cheat. In the school spirit evaluation, the fraternity loses points when Frank unsuccessfully attempts to jump through a ring of fire while dressed as the school mascot. He catches fire, resulting in a couple of firefighters being summoned.
Afterwards, Megan confronts Pritchard, telling him that she sabotaged the civilian fraternity's charter, but she wasn't accepted into Columbia Law School. Pritchard walks away, leaving Megan with nothing - but not before telling her, "I bribe people all the time, but I changed my mind. It's a free country, okay? Lesson learned."
Burned and humiliated, Frank rallies to give a strong performance in the floor exercise routine of the gymnastics competition. Bernard manages to complete the rings routine, leaving only the vault exercise remaining. Pritchard chooses Weensie, an obese member of the fraternity, to perform the vault. Weensie executes a perfect landing, allowing the fraternity to pass gymnastics.
The fraternity completes the activities with an 84% average. However, Pritchard tells them that their average has dropped to a failing 58% after accounting for the absence of Blue. While the students are in despair, Megan arrives with tape recorded evidence of Pritchard's bribery. After a chase throughout campus, Frank obtains the tape and uses it to get Pritchard fired. The fraternity's charter is reinstated and moves into Pritchard's former residence.
Nicole visits Mitch as he moves out of the old fraternity house, and tells him she dumped Mark after catching him cheating. The two reconcile, intent on moving their relationship forward. Mitch and Bernard decide to withdraw from the fraternity. Frank, now divorced, takes over the leadership role.
Luke Wilson as Mitch "The Godfather" Martin
Will Ferrell as Frank "The Tank" Ricard
Vince Vaughn as Bernard "Beanie" Campbell
Jeremy Piven as Dean Gordon "Cheese" Pritchard
Ellen Pompeo as Nicole
Juliette Lewis as Heidi
Leah Remini as Lara Campbell
Allen Haff as Frat Boy
Perrey Reeves as Marissa Jones
Craig Kilborn as Mark
Patrick Fischler as Michael
Sara Tanaka as Megan Huang
Simon Helberg as Jerry
Seann William Scott as Peppers
Elisha Cuthbert as Darcie Goldberg
Patrick J. Adams as Patch
Patrick Cranshaw as Joseph "Blue" Pulaski
Rick Gonzalez as Spanish
Jerod Mixon as Weensie
Matt Walsh as Walsh
Artie Lange as Booker
Rob Corddry as Warren
Todd Phillips as Gang Bang Member
Bryan Callen as Avi, the Waiter
Harve Presnell as Mr. Springbrook
Snoop Dogg as Himself
James Carville as Himself
Warren G as Himself
Kokane as Himself
Terry O'Quinn as Goldberg (uncredited)
Andy Dick as Oral Sex Instructor (uncredited)
Bishop Don "Magic" Juan as Himself
Abdul Goznobi as Abdul
Ashley Jones as Caterer
Arthur Taxier as Professor
Kristina Hughes as Topless Girl
Bob Lazar as Marissa's dad