Thirteen years after graduating 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) have moved on with adult life and responsibilities. Jim is married to Michelle (Alyson Hannigan) and they have a two-year-old son. 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 has supposedly gone missing, and Stifler works as a temp at an investment firm.
When a “Class of 1999″ high school reunion in East Great Falls is announced, Jim and Michelle arrive at Jim’s old home, where his father Noah (Eugene Levy) is now a widower. Jim encounters his neighbor Kara (Ali Cobrin), who he used to babysit and is soon to turn 18. Jim meets up with Oz, Kevin and Finch at a bar, where they meet Selena (Dania Ramirez), a former classmate and Michelle’s friend from band camp. Stifler unknowingly happens across the group, and joins them for weekend activities.
The next day, the group goes to the beach. Oz meets Heather (Mena Suvari), who is dating a heart surgeon named Ron (Jay Harrington), while 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 Stiflerdefecating in their beer cooler and destroying their jet skis. That night, the guys and girls, minus Michelle, go to the falls where they encounter a high school party celebrating Kara’s birthday. Jim is forced to drive an intoxicated Kara home, who tries to seduce him. Oz, Finch, and Stifler come help Jim secretly return Kara back home past her parents, but A.J. spots them sneaking out. A hungover Kevin wakes up in a bed next to Vicky naked and assumes they had sex.
The next day, Stifler tries to throw a party like in high school, but finds everyone else has outgrown this. Jim and Michelle, who have been having a lackluster sex life, attend with a plan to recreate their prom night. They bring Noah to help him out of his depression, who becomes intoxicated and encounters Stifler’s mother Jeanine (Jennifer Coolidge). Kevin confronts Vicky about the night before, but she discloses it was not sexual and is upset that he would assume such a thing. Mia takes ecstasy while Ron humiliates Oz by showing a DVD of his loss as a contestant on Celebrity Dance-Off. When Heather goes to comfort Oz, they attempt to rekindle their previous relationship, but are interrupted by Mia, who gets in a fight with Heather. Jim and Michelle decide to role play, but Jim is confronted by Kara wanting to seduce him again, followed by a hostile A.J. and his friends. The two conflicting groups have a fight on the front lawn, which is disrupted by police officers, who arrest Finch for stealing a motorcycle.
Mia leaves Oz, Stifler decides skip the reunion for work, and Michelle goes to her grandmother’s. When Jim tells his father about their lack of sex, he is told they need to make time for each other. At the reunion, Finch admits that he is an assistant manager at Staples and stole the motorcycle from his boss when he didn’t receive a raise that was promised. The boys get Stifler, who quits his job and attends the reunion. Kevin reconciles with Vicky, Finch gets together with Selena, Oz reunites with Heather, and Jim reconciles with Michelle. Stifler is asked to be a party planner for a wedding for his former lacrosse mates and hooks up with Finch’s mother Rachel (Rebecca De Mornay).
The next morning, the friends gather at Dog Days, where Jim encounters Kara and both apologize for their behavior. Oz plans to stay in town with Heather, Finch plans a trip with Selena to Europe, and Stifler plays coy about Finch’s mom. They all agree to gather once a year to catch up. Elsewhere, Noah and Jeanine are at a movie where Jeanine performs fellatio on him.