To celebrate his upcoming marriage to Tracy, Doug travels to Las Vegas with his best friends Phil and Stu, as well as Tracy’s brother Alan, in Doug’s future father-in-law Sid’s vintage Mercedes-Benz W111. They check into a hotel suite in Caesars Palace, and celebrate with a few drinks on the hotel rooftop. The next morning, Phil, Stu, and Alan awaken to find they have no memory of the previous night. Doug is nowhere to be found, Stu’s tooth is missing, the suite is in disarray, a tiger is in their bathroom, a chicken is in their living room, and a baby is in the closet. They see Doug’s mattress impaled on a statue outside of Caesars Palace and when they ask for their Mercedes, the valet delivers an LVPD police cruiser.
Using clues to retrace their steps, the trio travel to a hospital where they discover they were drugged with Rohypnol, known as roofies, causing their memory loss, and that they went to the hospital from a chapel the previous night. At the chapel, they learn that Stu married a stripper named Jade, despite being in a long-term relationship with his domineering and philandering girlfriend Melissa. Outside the chapel, the trio is attacked by gangsters saying they are looking for someone. They flee and track down Jade. They are then arrested by the police for having stolen a police cruiser. After being told that the Mercedes has been impounded, the trio are released when they unknowingly volunteer to be targets for a taser demonstration. While driving the Mercedes, they discover a naked Chinese man named Mr. Chow in the trunk. Chow jumps out of the trunk, beats the trio up with a crowbar and flees. Alan confesses that he drugged their drinks to ensure they had a good night, believing the drug to be ecstasy.
Returning to their suite, they find the boxer Mike Tyson, who orders the trio to return his tiger to his mansion immediately. Stu drugs the tiger, loads it into the Mercedes, and drives towards Tyson’s home. However, the tiger awakens midway and attacks them, clawing Phil on the neck and damaging the car’s interior. After pushing the car the rest of the way to the mansion, they deliver the tiger to Tyson. While driving back, their car is intentionally t-boned by a black Cadillac Escalade. The passengers are revealed to be the gangsters from the chapel, and their boss Chow. Chow accuses the trio of kidnapping him and stealing $80,000 in poker chips. As the trio denies this, Chow tells them he has Doug, and threatens to kill him if it is not returned. Unable to find Chow’s $80,000, Alan, with help from Stu and Jade, uses his knowledge of card counting to win $82,400 playing blackjack.
The next morning, they meet with Chow in the desert and exchange the chips for Doug, only to find this Doug is the black drug dealer who accidentally sold Alan the roofies. With Doug’s wedding set to occur in five hours, Phil calls Tracy to tell her that they cannot find Doug. Meanwhile, in discussion with Stu, “Black Doug” mentions that someone that takes roofies is more likely to end up on the floor than on the roof; Stu suddenly realizes where Doug is before Phil can reveal Doug’s disappearance to Tracy. The trio travels back to Caesars Palace where they find a dazed and sunburned Doug on the roof. They realize that they had moved him there on his mattress the previous night as a practical joke but immediately forgot when the roofies wore off. Doug had thrown the mattress onto the statue in an attempt to signal help. Before leaving, Stu makes arrangements to go on a date with Jade the following week. With no flights available back to Los Angeles, the four quickly drive home to make the wedding. Despite their late arrival, Doug and Tracy are married. At the wedding, Stu angrily breaks up with Melissa, having grown tired of her personality. As the reception ends, Alan finds Stu’s digital camera containing photos of the events from the night in Las Vegas, and the four agree to look at the pictures together before deleting them.