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The film starts in a maximum security prison south of Bangkok, as three guards run toward an intense riot happening between the prisoners. The main guard heads to a prison cell with a poster of a kitten. He looks behind the poster to find a big hole. Turns out Leslie Chow (Ken Jeong) escaped Shawshank-style. Chow runs out through a tunnel when he is suddenly flushed out of the sewers.

We shift to Alan (Zach Galifianakis) driving with a newly purchased giraffe. He's excited and the other drivers are surprised to see a giraffe on the highway. Their surprise turns to terror when Alan drives under a bridge and the giraffe is decapitated. It's head hits a family car, causing a big pile-up. Alan is reprimanded by his father Sid (Jeffrey Tambor), but Alan has a cavalier attitude about his actions. He drowns his father out as he continues rambling but doesn't see that Sid is collapsing from a heart attack.

Cut to Sid's funeral. Alan sings "Ave Maria" in a remarkably operatic voice. He gives a speech making up that his father's last words were "I'm proud of you, Alan. Never change." Alan vows to abide by those words, which upsets his mother. Later, Phil (Bradley Cooper), Stu (Ed Helms), and Doug (Justin Bartha) walk, and Doug mentions that Alan's been off his meds for almost six months, which explains his extremely impulsive behavior. He says that Alan's mother Linda (Sondra Currie) wants to set up an intervention and they know Alan will only listen if Phil and Stu are there. The two reluctantly agree.

The guys have dinner with their wives and discuss a place to send Alan. Phil makes thinly veiled jokes to Stu about his experience in Bangkok. As they leave, somebody watches them from closeby.

Tracy (Sasha Barrese) brings Alan home to the intervention, which also includes Alan's old housekeeper, and two other friends. Linda starts to say some words, but Alan is incredibly rude to her, and then the housekeeper. Doug then tells Alan about a rehabilitation center called New Horizons. They appeal to him by making it sound interesting and telling him that Doug, Phil, and Stu will take him. Alan asks Phil if he's really going, and Phil responds that he loves him. Cue Alan bawling like a baby.

The next day, the guys travel to Arizona to drop Alan off. He says he doesn't want to go anymore and tries to steer Phil's minivan back, but they're hit by a truck, causing them to swerve and crash off the road. Out of the truck come a couple of guys wearing pig masks. They jump the guys and kidnap them.

They're taken to the middle of the desert where one of the pig men is Black Doug (Mike Epps), the incompetent drug dealer from the first film. Out comes his boss Marshall (John Goodman). He informs the guys that he is looking for Chow. Naturally, the guys don't know where the hell he is, and neither does anybody else. Marshall tells them that ever since Alan met Black Doug outside a liquor store to grab drugs, a chain of events were set in motion. His gang stole $42 million in gold bricks from a sheik coming in from Abu Dhabi, and they were split up $21 million each. Chow stole from one car posing as a cop. When he was arrested in Bangkok, Marshall tried to negotiate with him to get him out in exchange for the gold, but Chow mocked him. They also learn that Alan's been keeping in touch with Chow through letters. Marshall declares that it is up to the Wolfpack to find Chow, and he takes Doug as collateral. He leaves them with Phil's minivan.

While at a gas station, Alan tells Phil that he got an e-mail from Chow, saying he's close. Phil decides they need to find Chow and drug him. They use Stu to purchase drugs from a pharmacy using his dental license, which almost doesn't work. Alan gets another e-mail from Chow asking him to meet him alone in Tijuana.

The Wolfpack drives to Mexico. Alan goes to meet with Chow alone, but he discovers Phil and Stu watching from far away. He appears threatening but Phil and Stu make Chow believe they missed him. They take him to a bar where he starts to sing karaoke. Stu tries to drug Chow's drink, but he catches a glimpse of this. Before he takes a drink, he attacks Stu and threatens to cut his neck, forcing Phil to tell the truth about their mission.

Chow takes the guys to a hotel where he tells them he owns a villa in Mexico where he is hiding the gold. Alan asks a stupid question regarding the plan, and then trips and falls, causing a few roosters that Chow uses for cockfighting break out, attacking the guys. They throw three of them out, but Chow smothers one to death.

Chow leads the Wolfpack to the villa for the gold. They drug the guard dogs and get inside. Chow tells them they need to disarm the system to break in. He and Stu crawl through the kitchen and try to cut wires, but Chow realizes he is colorblind (and also dyslexic). They successfully cut the wires and bring Phil and Alan to the basement, where Phil breaks through the brick wall with a sledgehammer to get the gold out. Unfortunately, once the gold is out, Chow locks the guys in the basement, takes the gold, and sets off the alarm.

The Wolfpack is arrested by Mexican police, who have them detained. Moments later, the charges are dropped. The guys are taken in a limo back to the villa to find Marshall there, along with Doug and Black Doug. The villa was really Marshall's, and Chow apparently stole the rest of Marshall's gold. To top it off, Chow killed the guard dogs by snapping their necks on the way out. Marshall grabs a gun and says somebody has to pay. Black Doug grabs Doug, but Marshall shoots Black Doug in the chest and kills him because he was the head security and failed him. Marshall gives the Wolfpack another chance to find Chow. He gives them the limo to find him.

Stu suggests that they locate Phil's minivan to find Chow, but Phil's phone is in there. Alan tells them he has an app on his phone to locate another phone. Phil uses the app to find out that the phone is in none other than Las Vegas.

The guys make it to Vegas and find the minivan parked outside a store where gold is exchanged for cash. They meet the clerk, Cassie (Melissa McCarthy), who is just as crazy as Alan. She tells them Chow came in and got money for the gold and went to get girls. She gives them a card for an escort service. Before they leave, Alan shares a romantic connection with Cassie. Outside, Stu calls the service but they don't know anything. Phil determines they have to talk directly to an escort. Stu knows who he's talking about.

They go to the house of Jade (Heather Graham), the hooker Stu accidentally married. She's pregnant again and living in a nice house with her husband. While Phil and Stu go with Jade to get information, Alan finds Jade's son Tyler (aka Baby Carlos), now 4 years old. Alan sits with him and makes the boy think he is his real father. This leads to a tender moment between the two with Alan realizing he let his own father down. Meanwhile, Jade learns that Chow is at a hotel with hookers and drugs. The guys prepare to leave, but Tyler goes to hug Alan. He gives him the aviator glasses he wore in the first film.

The Wolfpack calls Marshall to tell him they know where Chow is. He tells them to meet him in a location outside in the desert at 8:00 the next morning for a drop-off. The guys go to the Caesar's Palace hotel they stayed at the last time. Phil and Alan grab blankets and make a rope so they can climb from the roof into Chow's room, which is identifiable by the strobe lights. Phil manages to climb down safely but the rope comes loose for Alan and he falls on the Caesar's sign. Phil tells him to jump and he will catch him. Alan jumps and nearly falls over the edge but Phil grabs him. The two go into the hotel to find Chow, but he outruns them and jumps out the window with a parachute. Phil calls Stu and tells him to follow Chow. Stu rushes through the city in the limo, eventually having Chow land on the limo. Stu breaks and throws Chow off, thinking he's killed him, but he's okay. He stuffs Chow in the trunk and goes back for Phil and Alan, who took the gold from his room.

On their drive to the desert, Chow tells the guys he spent the half of the gold he stole previously all in Bangkok. When they get to the drop-off, they hand Marshall the gold and he safely gives Doug back to them. He then shoots the trunk, thinking he's killed Chow, to the horror of Phil and Stu. He opens the trunk to find no body. He aims at the Wolfpack, but Chow springs from the sunroof and shoots Marshall and his goon in the back, killing them and uttering his famous "Toodaloo, mothafuckas!" line. He aims the gun at Phil but Alan steps in front of him. Chow relents when he decides that Alan was a friend by unlocking the latch between the trunk and backseat to let Chow free.

The next morning, Chow takes the gold and stuffs Marshall and his goon in the trunk. He offers Alan a gold brick but he refuses, and then makes an anti-Semitic joke at Stu's expense for the hell of it. Alan then breaks off his friendship with Chow because people get hurt when they get together. Chow says it's still funny but Alan makes it clear they are done. They drive off and leave him alone.

The guys make it to where they left Phil's minivan, in front of Cassie's store. Alan decides to stay, letting the other three go home. He goes in the store to meet with Cassie, offering to take her to the Paris Hotel and Casino. She's banned from there but says she'd like to go to the Golden Nugget. Alan agrees. They awkwardly kiss and he pulls his pants down because "he saw it in a pornography", but Cassie says they should do that later.

Six months later, Alan is getting married to Cassie. Phil, Doug, and Stu meet with him. Alan says he is resigning from the Wolfpack to spend more time with Cassie (which the guys understand and are a little thankful for), but says they should meet again every now and then. They leave for the wedding, doing one more badass group walk as the Wolfpack just like always.

During the credits, we see after the wedding what looks like a really messed up scene in a hotel. Phil wakes up to the mess while Alan is sleeping next to Cassie. Stu comes out laughing...and with a real pair of breasts. Phil tells him not to freak out, but he does. Alan says there were drugs in the wedding cake...from Chow. Not surprisingly, Chow comes out in the nude with a samurai sword doing his maniacal laugh. Then the drug-dealing monkey from the second film falls from the ceiling on top of Stu, causing him to scream.

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