Two years after the events in Bangkok, Leslie Chow (Ken Jeong) escapes from a maximum security prison, using a riot as cover. Meanwhile in America, Alan Garner (Zach Galifianakis) causes a 20-car freeway pileup after he purchases a giraffe and accidentally decapitates it on a low bridge. Alan's father Sid (Jeffrey Tambor), furious with Alan for never owning up to his mistakes, dies of a heart attack in the middle of a lecture. After the funeral, Alan's brother-in-law Doug Billings (Justin Bartha) informs friends Phil Wenneck (Bradley Cooper) and Stu Price (Ed Helms) that Alan has been off his ADHD medication and is out of control. They attend an intervention, in which Alan agrees to visit a rehab facility in Arizona, so long as "the Wolfpack" takes him there. On the way to Arizona, Phil's minivan is rammed off the road by a rental truck and the group is taken hostage. They are later confronted by mob leader Marshall (John Goodman) and "Black Doug" (Mike Epps), his head of security.
He tells them that Chow hijacked half of a $42 million gold heist and, seeing how Alan has been the only one to communicate with Chow during his imprisonment, deduced that the Wolfpack could locate him and retrieve the gold. Marshall kidnaps Doug as collateral and gives the others three days to find Chow, or else Doug will be killed. Alan sets up a meeting with Chow in Tijuana, Mexico, where Stu and Phil will hide and attempt to drug him. However, Alan gives away their location and he forces them to confess they are working for Marshall. Chow explains his plan to retrieve the stolen gold from the basement of a Mexican villa he previously owned. Stu, Alan and Phil break into the house and successfully retrieve the gold, but Chow double-crosses them by locking them in the basement, rearming the security system and escaping in Phil's minivan. They are arrested but mysteriously released from the police station, where they are picked up by a limousine and taken back to the villa, where they meet up with Marshall.
They learn that Chow had lied to them; the villa was never his and the gold they stole was the other half he didn't get from Marshall. Marshall forgives them for their mistake but kills "Black Doug" for his incompetence and reminds them of their now two-day deadline. The group tracks Phil's phone, which was left in the minivan, outside a pawn shop in Las Vegas. The pawnshop owner, Cassie (Melissa McCarthy), tells them that Chow traded a gold brick for $18,000, far less than its usual sell rate of $400,000. Using Stu's former lover Jade (Heather Graham) as their contact, they learn that Chow is barricaded in the penthouse suite of Caesars Palace. Phil and Alan sneak into his suite from the roof, but Chow escapes, jumping from the balcony and parachuting down to the strip. Stu catches up to Chow and locks him in the trunk of the limo that Marshall had lent to them. They take the gold and meet with Marshall, who releases Doug back to the group. Although Marshall initially promised to not harm Chow, he changes his mind and shoots through the trunk of the car, presumably killing him (which visibly affects the group). Luckily, Alan had freed Chow through a backseat compartment just moments earlier.
Chow emerges from the limo and kills Marshall, allowing the Wolfpack to live because Alan had saved his life. He offers Alan a bar of gold as a gift, but Alan turns him down, and ends their friendship due to Chow's unhealthy influence on the group. As Chow sadly watches them leave, they go to retrieve Phil's minivan from the pawnshop and Alan makes a date with Cassie. Six months later, the two marry. Vowing to begin taking responsibility for his actions, Alan regretfully resigns from the Wolfpack, but would still like for the gang to hang out on occasion. As the four walk to the ceremony, a montage of clips from the previous films play, thus ending the film. In a post-credits scene taking place the morning after the wedding, Alan, Cassie and Phil appear to have staged another wild party that they cannot remember. Stu emerges from the bathroom with breast implants and Alan remembers that the wedding cake was a gift from Chow, who emerges from the next room naked, laughing and wielding a Katana