Two years after their escapade in Las Vegas, Stu (Ed Helms), Phil (Bradley Cooper), Doug (Justin Bartha), and Alan (Zach Galifianakis) are traveling to Thailand to celebrate Stu's wedding to his fiancée, Lauren (Jamie Chung). Much to Alan's dismay, they are joined by Lauren's younger brother, Teddy (Mason Lee), a prodigy and pre-medical student at Stanford University. At the wedding reception, Lauren's father shows his disapproval of Stu by comparing him to rice porridge in his toast. At the end of the night, Stu hesitantly joins Phil, Doug, Alan and Teddy for a beer. Sitting at a campfire and roasting marshmallows, the group toast to Stu and Lauren's future happiness.
The following morning, Phil, Stu and Alan, along with gangster Leslie Chow (Ken Jeong) (whom Alan befriended after Las Vegas) and a chainsmoking capuchin monkey, awaken in a dirty hotel room in Bangkok. Stu has a face tattoo, and Alan's head is completely shaven. However, they cannot find Teddy, only discovering his severed finger. Chow begins recalling the events of the prior night, but his heart stops after snorting a line of cocaine. Panicked, the trio dispose of Chow's body in an ice machine.
Through Doug (who left early the preceding night and is still at the resort where the wedding is to be held), they find out that Teddy is waiting in jail. Upon arriving at the prison, they are given a handicapped elderly Buddhist monk, who has taken a vow of silence. The trio and the monk travel to a bar after finding a business card only to see the entire neighborhood smouldering in ruins. They enter a nearby tattoo parlor, where they are told that they had started a fight in the club that escalated into a riot. The trio then return the monk to his Buddhist temple, where they are encouraged by the head monk to meditate to help remember past events. Alan is able to recall a strip club that they had gone to. There, they learn that Stu had engaged in sex with a katoey prostitute at the bar (with Stu being on the receiving end). Upon exiting, the trio are attacked by two Russian mobsters from whom they had apparently stolen the monkey, and Phil is shot in the arm.
After Phil is treated at a clinic, Alan confesses that he had drugged some of the marshmallows from the previous night with muscle relaxants and ADHD medication in order to sedate Teddy but accidentally mixed up the bags. Stu attacks Alan leading them to notice an address and time point for a meeting written on Alan's stomach. The trio arrive at a luxurious hotel to find another gangster, Kingsley (Paul Giamatti), who demands Chow's bank account code and password by the next morning in exchange for Teddy. They return to the hotel to try to find Chow's password, only to discover that he is still alive. After Chow explains that he had hidden the code in the monkey's jacket, they steal the monkey back from the Russian mobsters through a violent car chase, during which the monkey is shot and injured. After taking the code and leaving the monkey at a veterinary clinic, the group return to Kingsley's hotel to complete the deal. Suddenly, Interpol agents appear and arrest Chow. Kingsley turns out to be an undercover agent, who tells the trio that the police have searched all day for Teddy but were unable to find him.
Desperate and out of clues, Phil once again calls Doug's wife Tracy to inform her of their dilemma. Stu then has an epiphany and realizes that Teddy must have woken up in the middle of the night to get more ice for his severed finger (after the first bucket of ice had melted) but became trapped after the power went out while he was ascending. The trio rush back to the hotel and find Teddy in the elevator unharmed (albeit still missing a finger). The four use Chow's speedboat, the keys for which were in Teddy's pocket, to travel back to the wedding reception. Arriving just as Lauren's father is about to cancel the wedding, Stu makes a defiant speech where he rejects being boring and instead states that he is in fact quite wild. Impressed by Stu's sudden display of authority and confidence, Lauren's father finally accepts him and gives the couple his blessing. After the wedding continues on, Alan presents Stu with a special gift at the post-reception dance: a musical guest performance by Mike Tyson. Later at night as Phil, Stu, Alan, Doug, and Tyson reminisce about all of their crazy escapades, Teddy discovers that he had taken many pictures during the night on his mobile phone. Once again, the group agree to look at the pictures together once before erasing the evidence of their exploits