In California, Alan (Zach Galifianakis) causes a major traffic accident after accidentally decapitating his pet giraffe under a low bridge. Soon afterwards, Alan's father (Jeffrey Tambor), furious with him for never owning up to his mistakes and believing that he could get away with anything, has a heart attack and dies. Following the funeral, Doug (Justin Bartha) convinces Stu (Ed Helms) and Phil (Bradley Cooper) to attend an intervention in response to the fact that Alan is off his ADHD medication and is out of control. Alan agrees to visit a rehabilitation clinic in Arizona after Doug promised that the Wolfpack would go with him.
While en route to the facility, gangster Marshall (John Goodman) and Black Doug (Mike Epps), his head of security, run Phil's minivan off the highway and kidnap the group. Marshall informs them that, during a $42 million gold heist, Chow stole half of the loot and has escaped from prison. Marshall take Doug as a hostage and demands that the rest of the Wolfpack find Chow and get the stolen gold back.
Chow communicates with Alan, setting up a meeting location in Tijuana for just the two of them. Stu and Phil arrive in secret, planning to drug Chow with Demerol, but Alan gives away their location. After lying to Chow, the group visit a karaoke bar, where Stu attempts to drug Chow's drink. Smelling the Demerol, he forces the group to confess that they are working for Marshall. Chow later agrees to retrieve the stolen gold from his former house, a Mexican villa that was foreclosed upon after he was arrested, and reveals that the first half had already been spent in Bangkok. After elaborately entering the house, which included drugging the two guard dogs and disabling the security system, and retrieving the gold, Chow double-crosses them by locking the group in the basement, tripping the house alarm and escaping in Phil's minivan. The three are arrested, and are soon after released after the charges were mysteriously dropped. They are forced into a limo waiting outside the police station, which takes them back to the villa they had broken into. It is revealed that the villa is actually Marshall's, Chow had never lived there, and the gold they helped him steal was the half Marshall had saved. Infuriated by the proceedings, Marshall kills Black Doug and demands that the three track down Chow again, leaving them the limo to drive.
After Phil realizes that he left his cell phone in the minivan, he uses an app on Alan's phone to locate the phone and, as a result, Chow. Phil and Stu grimace to learn that Chow fled to Las Vegas. After finding the minivan abandoned outside a small pawn shop, the three speak to its owner, Cassie (Melissa McCarthy), who tells them that Chow traded a gold brick for much less than it was worth to finance a stream of hookers and drugs and gives them the business card of the escort service she gave to Chow. After the service refuses to give Stu any information, they get in touch with Jade (Heather Graham), who is now pregnant with her second child, and uses her prior connections in the business to inform them that Chow has walled himself up in the penthouse suite of Caesars Palace and has security agents at the door. Alan and Phil pursue him by clumsily lowering themselves onto his balcony from the roof. Planning once again to drug him, he attacks Phil and escapes, parachuting from the balcony. Stu follows Chow as he flies over Las Vegas, landing atop the limo and causing Stu to crash.
Stu stashes the incapacitated Chow in the trunk of the limo and picks up Phil and Alan from Caesars. They throw the remaining gold in the backseat and meet Marshall in the desert at sunrise. After checking the gold, he releases Doug to the group and unloads his gun into the trunk of the limo, seemingly killing Chow. Alan, however, had secretly opened a compartment in the backseat, allowing Chow to shoot Marshall and his henchmen right as they discover Chow had escaped the trunk. He goes to shoot them, but decides not to, acknowledging that Alan was the only one of the group that helped him. Chow offer Alan a piece of gold as a gift for his help and seems intent to reunite again in the future, but Alan turns him down after admitting that Chow is an unhealthy influence on him. Alan bids farewell to Chow for the last time. The group return to Vegas to retrieve Phil's minivan and return home, although Alan stays behind to ask Cassie out on a date, kissing her.
Six months later, Alan prepares for his wedding to Cassie with Doug, Stu and Phil. He acknowledges that he must now take responsibility for himself and resigns from the Wolfpack, although he makes weekly plans for the group to gather. As the group walks to Alan's wedding, a brief montage plays, showing the group of four in various settings from the previous films.
A mid-credits scene depicts Alan, Cassie and Phil waking up in a hotel room left in disarray, unable to remember the events of the previous night. Stu emerges from the bathroom, unaware that he now has breast implants, as Alan reveals that Chow had bought the wedding cake. Chow then appears naked from another room, commenting that the group had yet another "sick night," as the Capuchin monkey from the previous film drops on Stu's head.
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