Thirteen years after graduating from high school, Jim Levenstein (Jason Biggs), Chris “Oz” Ostreicher (Chris Klein), Kevin Myers (Thomas Ian Nicholas), Paul Finch (Eddie Kaye Thomas), and Steve Stifler (Seann William Scott) are well-established in their lives and careers. Jim lives in the Chicago area and is still married to Michelle (Alyson Hannigan) and now has a two-year-old son, Evan. Since the birth of their son, Jim and Michelle’s sex life has deteriorated. Oz is an NFL sportscaster living in Los Angeles with his supermodel girlfriend Mia (Katrina Bowden). Kevin is married to Ellie and works from home as an architect. Finch tells his friends that he has been travelling the world, and still searching for his one true love. Stifler works as a temp at an investment firm, where he is also the victim of humiliating verbal abuse by his cold-hearted employer.
Former classmate John (John Cho), one half of the ‘MILF’ duo, organizes a Class of 1999 high school reunion in East Great Falls. Jim and Michelle return to Jim’s old home, where his father Noah (Eugene Levy) is now a widower. Jim encounters his neighbor Kara (Ali Cobrin), whom he used to babysit and who is soon to turn 18. Jim meets Oz, Kevin, and Finch at a bar, where they meet Selena Vega (Dania Ramirez), Michelle’s best friend from band. Stifler appears unexpectedly, and joins them for weekend activities.
The next day, the group goes to the beach. Oz meets his high school girlfriend, Heather (Mena Suvari), who is dating a cardiologist named Ron (Jay Harrington), and Kevin reconnects with Vicky (Tara Reid). The guys have an altercation with Kara’s boyfriend, A.J., (Chuck Hittinger) and his friends, which ends with Stifler defecating in their beer cooler and destroying their jet skis. That night, most of the group go to the falls and find a high school party celebrating Kara’s birthday. Finch and Selena reconnect, and they fall in love. Kara gets drunk; Jim drives her home, and she tries to seduce him. They are discovered by John, who simply mistakes Kara for Michelle. Oz, Finch, and Stifler help Jim return Kara to her parents’ home, but A.J. spots them. Kevin wakes up hungover next to Vicky and assumes they had sex.
Jim and Michelle attend a party thrown by Stifler, hoping to recreate their prom night, and bring Noah along. Noah gets drunk and encounters Stifler’s mother Jeanine (Jennifer Coolidge) for the first time. Kevin confronts Vicky about the night before, but she insists there was no sex. Mia takes ecstasy, and Ron humiliates Oz. A newly sympathetic Heather comforts Oz, and they reconcile. They are interrupted by Mia, who starts a fight with Heather. Stifler performs oral sex on a former classmate named “Long Lips” Loni hoping she would return the favor, only to strike out. By this point in the story, Jim has told Kara that he does not care about her. A fight ensues between A.J. and his gang against Jim and his friends, which is disrupted by police. But the police only arrest Finch for stealing a motorcycle, which Stifler finds amusing. Exasperated by Stifler’s immaturity, the guys blast him, and finally admit that they did not want him to ruin things like he always does. Distraught, Stifler ends the party.