Doug (Justin Bartha) is about to be married, so his friends — Phil (Bradley Cooper), a schoolteacher bored of the married life, Stu (Ed Helms), a dentist with a strict and controlling girlfriend, and Doug's eccentric, socially-inept soon to be brother-in-law Alan (Zach Galifianakis) — take him to Las Vegas for a bachelor party. Stu's girlfriend (Rachael Harris) constantly calls him, forcing him to lie to her about their location.
The four friends get a suite at Caesars Palace, then sneak onto the roof of the hotel and toast to the night ahead. The next morning, the three groomsmen awake in the suite with no memory of the previous night. They realize Doug is missing, Stu has lost a tooth, there's a tiger in the bathroom, a baby in the closet, and the suite's a wreck. Initially they believe Doug has gone for breakfast, but worry when they find his phone still in the room. Alan discovers Stu's tooth in his pocket and a VIP parking pass, and Stu finds an ATM receipt for $800. Outside the hotel Stu inquires as to why there is a mattress impaled on a statue, and a taxi driver tells him, "Some guys just can't handle Vegas." The valet brings the groomsmen a police car that they dropped off the night before.
Discovering that Phil is wearing a hospital bracelet, the guys head to the hospital and learn that they had roofies in their blood, explaining their memory loss. Their doctor tells them they came from a wedding at the "Best Little Chapel". At the chapel they learn that Stu married a girl named Jade (Heather Graham) and gave her his grandmother's Holocaust ring in the ceremony, which he had intended to use to propose to his girlfriend after Doug's wedding. In the parking lot they are attacked by two Asian thugs who smash their car windshield and shoot the chapel owner in the shoulder. The men escape and track down Jade, who turns out to be the baby's mother and works as an escort and stripper. Cops burst into her apartment to arrest the three men for stealing their police car. Phil points out the potential embarrassment for the officers if the story of their lost squad car got out, so they work out a deal in which the men "volunteer" as targets for a taser demonstration. The three friends retrieve their car from an impound and search it for clues to Doug's whereabouts, but as they are driving back to the hotel, they hear a banging from the trunk. When they open it to investigate, they are attacked by a small, naked Asian man who then runs away. Alan admits to spiking their drinks the night before with what he thought was ecstasy, hoping they would have a better time, but realizes the drug dealer must have sold him roofies instead.
They return to the hotel to look for further evidence, but find former boxing champion Mike Tyson in their room, who knocks out Alan and orders them to return his tiger, which they stole from his mansion during the night. They give the tiger a steak laced with roofies so they can transport it, but on the way it wakes up and damages their car. They push the car the rest of the way to Tyson's home.
After returning the tiger and watching a tape from Tyson's security cameras of their activities from the night before, they are attacked again by the thugs, who, it turns out, are led by the man they found in the trunk of their car, Leslie Chow (Ken Jeong). According to Chow, they mixed up bags at a casino the night before, and the groomsmen have $80,000 of his money. Chow demands it back in exchange for Doug, whom he has kidnapped. Unable to find the money, Alan uses his knowledge of card counting to win it playing blackjack. The money is returned, but Chow had kidnapped a different Doug (Mike Epps), who turns out to be the drug dealer who sold Alan the roofies.
Stu realizes where Doug is after drug-dealer Doug questions the reasoning behind the term "roofies", saying they are more likely to leave you on the floor than on the roof. Stu deduces that the mattress they thought they had thrown from their hotel room must have come from the roof after he remembers that hotel windows do not open in Las Vegas, and therefore they must have locked Doug on the roof as a prank. They find him, heavily sunburned, with less than four hours before the wedding. Stu finds Jade before they leave to tell her that he can't stay married to her, but promises to come back the following weekend to see what develops between them. Stu also learns he lost his tooth because Alan bet him that he wasn't a good enough dentist to pull out his own tooth. Doug discovers he has $80,000 worth of casino chips in his pockets as they rush home and make it to the wedding. Phil goes back to his family, while Stu breaks up with his girlfriend.
As the wedding ends, the four friends reflect on their trip and express their desire to remember everything they did during the lost hours. When Alan discovers a camera they had with them depicting most of the outrageous events of their forgotten night, the four agree to look at the pictures exactly one time before destroying the evidence.
