American dentist Stu (ED HELMS) is all set to marry his fiancée, Lauren (JAMIE CHUNG), in her homeland of Thailand, and has invited his friends, Phil (BRADLEY COOPER) and Doug (JUSTIN BARTHA), to come along for the big day. But he's extremely reluctant to offer a similar invite to Doug's "stay-at-home-son" brother-in-law, Alan (ZACH GALIFIANAKIS), a passive-aggressive man-child who still lives at home with his parents.
Stu's reluctance stems from the group's previous experience in Las Vegas where, for Doug's bachelor party, Alan spiked everyone's drinks with roofies, thus leading to a wild and dangerous night where no one could remember anything that happened. To make matters worse, that also involved them trying to figure out what happened to Doug who went missing, all while dealing with boxer Mike Tyson; Stu ending up married to a stripper; and a jive-talking criminal, Mr. Chow (KEN JEONG), who claimed to have kidnapped Doug.
Despite all of that and due to Doug pleading for some family-related leniency, Stu agrees to have Alan tag along and they all set off for Thailand. There, they meet Lauren's family, including her stern father (NIRUT SIRICHANYA) who disapproves of Stu, especially in comparison to Lauren's 16-year-old, pre-med, cello-playing brother, Teddy (MASON LEE). The guys decide to take him out for the night before the wedding, and despite their precautions, the same thing happens again.
This time, however, rather than Doug disappearing, it's Teddy who goes MIA. All of which results in Stu, Phil and Alan trying to find him, all while dealing with the return of Mr. Chow, a drug-peddling capuchin monkey, a silent monk, and other figures and developments that threaten to derail Stu's pending wedding.