In Los Angeles, preparations for the lavish wedding of Tracy and Doug are underway at Tracy’s parents’ mansion. Hours before the ceremony, all is in readiness, except that Doug, his groomsmen Phil and Stu, and Tracy’s brother Alan have not returned from their bachelor party in Las Vegas. When Tracy calls the men’s cellphones, she gets only voicemail. Eventually, a disheveled Phil telephones from the Mojave Desert and confesses that they have “lost” Doug. Tracy reminds him that the wedding begins in five hours, but Phil tells her simply, “that’s not gonna happen.” Two days earlier, while being fitted for their tuxedos, Doug assures the socially awkward Alan that he wants him to come to Las Vegas with his longtime friends: Doug tells Alan that they will now be brothers, and touched, Alan promises never to tell what happens there, then hugs Doug. Tracy’s father, Sid, also wishes the best for Doug and lends him his vintage Mercedes convertible for the drive to Las Vegas. Knowingly, Sid tells Doug that what happens in Vegas stays in Vegas, but adds that herpes is an exception. At the school where he teaches, Phil collects money from his students for an upcoming field trip and places all of it in an envelope marked, “Vegas.” After school, he rendezvous with Doug and Alan, who are waiting for him in the Mercedes. Meanwhile, Stu, a dentist, is at home packing and half-listening to his domineering girlfriend, Melissa, as she expresses disapproval of bachelor parties. Stu mollifies her by agreeing. Claiming falsely that the bachelor party is being held in the Napa Valley, he assures her that he will call as soon as possible. After picking up Stu, Doug, who is mindful of the Mercedes, drives carefully, allowing other cars on the highway to pass him. When Alan tells him it is safe to change lanes, Doug almost collides with a large truck, then swerves and narrowly escapes hitting a car in the opposite lane. This amuses Alan, as well as Phil, a husband and father who is eager to break loose and create mischief, but not Stu or Doug. Along the way, Alan reads a book about black jack and asks his companions if any of them wish to be his spotter. The others tell him that counting cards is illegal, but Alan suggests that it is only frowned upon. At a gas stop, Phil questions Doug about Alan’s persistently peculiar behavior. Although Doug admits Alan is odd, he says he is ok, but adds that he should be discouraged from gambling and drinking too much. Stu calls Melissa and carefully maintains the pretense that the men are on their way to Napa. After the call, Phil confronts Stu about his three-year relationship with Melissa, reminding him that she had sex with a bellhop on a cruise ship, but Stu argues that it was the bartender on the ship and that she did not actually complete the act. In Vegas, the men book a $4,200 per night luxury suite called the “Villa” at Caesars Palace. Because a credit card number is required to book the room, Stu nervously provides his, although he is fearful that Melissa, who routinely looks over his statements, will discover that he has been to Vegas. In the room, Stu phones Melissa, and describes the Villa’s opulent, high-tech decor as a quaint cabin with no phones or television. After hanging up, Stu shows his companions his grandmother’s ring, which he says she managed to keep all through the Holocaust, and announces his intention to propose to Melissa at the wedding reception. Believing Stu is making a big mistake, Phil points out that Melissa beats him up and had sex with a sailor on a cruise ship, but Stu argues that he deserved it and again points out that her sexual companion was a cruise ship bartender. Before leaving for a night on the town, Alan straps across his shoulder what Phil disparaging calls a “manpurse,” but which Alan explains is a “satchel” similar to one Indiana Jones owned. Breaking hotel rules, the men go up to the roof to see the extraordinary view of the city and drink Jagermeister beer, and Stu makes an impromptu toast to Doug’s impending marriage. Alan reads a prepared speech from a piece of paper that states that he was a “one-man wolf pack” until Doug joined his pack. Now, Alan says, Phil and Stu are in his pack, and together they can be wolves in the desert looking for strippers and cocaine. Startling them, he pulls out a knife, cuts his hand and says he wants to be blood brothers, but the others decline and Doug gently takes the knife away. Phil then toasts to a night they will never forget. The next morning, Stu awakens in the Villa, face down on the floor, oblivious of a chicken clucking nearby and a woman exiting the suite. Seeing the trashed and disheveled room, which appears to be the result of bacchanalian revelry, Stu worries about future charges on his credit card. Then, upon discovering that one of his incisors is missing, he worries about Melissa’s reaction. Alan awakens, and proceeds to the bathroom, where he discovers the presence of a live tiger. He flees from the bathroom and trips over Phil, who then awakens with a headache. Although they find Doug’s cell phone, Doug, as well as his mattress, is nowhere in the Villa. By following the sound of crying, Alan finds a baby in the closet. None of them can remember what happened the previous night. Stu is concerned about Doug, but Phil presumes he went out for food and proposes that they do the same. However, Doug is nowhere to be found downstairs. At a poolside table, Stu throws up and the others try to recall what happened the previous evening. They remember drinking Jagermeister on the roof, having dinner and playing craps, and they believe that Doug was with them. When Alan finds Stu’s tooth in his pocket, Phil tells them to check their pockets for clues. Stu finds an ATM receipt from the Bellagio hotel and Alan, a valet ticket at Caesar’s for 5:15 am, the time they apparently returned. When Phil notices that he has a hospital arm band on his wrist, they hope that medical records will indicate what happened to them. While waiting for the valet to retrieve the Mercedes, the men notice that Doug’s mattress has been impaled on the uplifted arm of the statue of Caesar in front of the building and conclude that it was thrown out of the window during the night. Their attention is diverted when the valet delivers a police cruiser to them, instead of the Mercedes. Using the lights and loudspeaker to clear the traffic ahead of them, Phil drives, occasionally on the sidewalk, to the hospital. There, a doctor remembers that four of them, including Doug, arrived at 2:45 a.m. without a baby. Although Phil was diagnosed with a mild concussion and bruised ribs, the doctor recalls that no one could explain how it happened. The doctor also says that a blood sample analysis reveals that Phil had in his system Rufinol, a date rape drug that causes memory loss. After the doctor remembers that they talked about a wedding they had attended at The Best Little Chapel, the men proceed there and are greeted as old friend by the proprietor, Eddie, who shows them pictures of Stu’s marriage to a woman called Jade. Eddie also brings out caps, mugs and calendars that Stu bought to commemorate the event and provides Jade’s address. When Melissa phones Stu to scold him for not calling her recently, he claims that the sequoias have been blocking the telephone signals. In the parking lot of the chapel, two thugs attack them, but Phil drives away, inadvertently over the foot of one of the men, who accidentally shoots Eddie. When they arrive at Jade’s apartment, she is relieved to see her baby and passionately kisses Stu, who is shocked to see that he gave her his “grandmother’s Holocaust ring.” Jade explains that she left the Villa early in the morning to get coffee, but when she returned they were gone. She confirms that Doug was with them at one a.m., which was the time she left for a few hours to perform her shift at the strip club. Unexpectedly, two police officers burst into the apartment and arrest the men for stealing their cruiser. At the station, Phil struggles with handcuffs to phone Tracy. He tells her they were given a complimentary extra night at the hotel and will drive back for the wedding early in the morning. In the interrogation room, the police inform them that the Mercedes was impounded after being found in the middle of Las Vegas Boulevard. When they are told that they will be held until Monday, Phil tells them about the wedding and asks to negotiate. Gleefully, the police officers decide to use the men as targets to demonstrate tasers to schoolchildren who are touring the station. After the children are allowed to shoot them with a stun gun, the men are released. They retrieve the Mercedes and are pleasantly surprised that it has not been damaged. Looking for more clues to Doug’s whereabouts, they find several intriguing items in the car, including a naked Asian man in the trunk. The man jumps out, beats them with a crowbar and runs away. As they recuperate, Alan confesses that he slipped Rufinol into their Jagermeisters, believing it was Ecstasy. When Alan adds that he just wanted them to have fun, Phil reasons that at least they know a stranger did not drug them. When they return to the Villa, the infamous boxing champion, Mike Tyson, who is singing along with the piped-in music, is waiting with his assistant, Leonard, and demands to know why his tiger is in their room. Mike gives them Doug’s coat, which he found on the tiger’s cage and which contained the room key that led him to the Villa. Mike knocks out Alan, orders them to return the tiger to his house within forty minutes then leaves. The men drug the tiger with a steak laced with Rufinol and, while waiting for the drug to take effect, Stu sings a song at the piano. Then they load the sleeping animal in the backseat of the Mercedes, but, on the way to Mike’s house, the tiger awakens. It tears the upholstery and, for their own safety, the men exit the car and push it the last mile. Mike and his bodyguard allow them to see security camera footage that confirms that the four of them were leading the tiger away at 3:30 a.m. After being forgiven by Mike, who is impressed that they stole a police car, they leave, but on the road they are stopped by an SUV that plows into them. The two thugs and the Asian man, now clothed, demand that they return the purse that Alan mistook for his own satchel when they were gambling the previous night. The Asian explains that his purse contained $80,000 worth of casino chips and, when he tried to get his purse back, Phil called him his “lucky charm” and threw him in the trunk. Menacingly, the Asian says that if they want Doug back, they must bring $80,000 in cash to Big Rock in the Mojave Desert at dawn. When the men cannot find the satchel in the Villa, they proceed to the black jack table, where Alan wins thousands of dollars. Aware that casino employees are about to accuse Alan of card counting, Jade, who has accompanied Stu, creates a diversion by falling off her chair, thus allowing Alan and Phil to cash out their chips without hindrance. In the car on the way to the desert, Alan reports that they won $82,400 and then makes up a song about the “three best friends that anyone ever had.” At the appointed place, the Asian tells them his name is Leslie Chow and exchanges Doug, who is tied up and covered with a sack, for the money. However, when the sack is removed, everyone discovers that Chow had kidnapped the wrong man. Although the victim is also named Doug, Alan recognizes him as the black man who sold him the Rufinol and “Black Doug” apologizes for unintentionally selling him the wrong product. Resigned that they cannot find Doug, Phil calls Tracy to tell her they will not return in time for the wedding. As they wait for him, Black Doug comments that “roofies,” which is a nickname for Rufinol, is a misnomer, because a user is more likely to end up on the floor than the roof. Suddenly enlightened, Stu tackles Phil, grabs the phone and tells Tracy they will be there soon. To the others, he explains that Doug’s mattress could not have been thrown out of the window, because Las Vegas hotel windows do not open. Therefore, he explains, Doug’s mattress was thrown from the roof, where they took Doug while he was sleeping, a prank similar to one they played on him when they were children. They rush to the hotel roof to find Doug, sunburned and groggy. After checking out of the hotel, Stu finds Jade waiting to return his grandmother’s ring. She tells him that he pulled out his own tooth on a dare, and the two of them schedule a date for the following weekend. Having three and a half hours before the wedding, the friends race to Los Angeles. During the drive back, Doug tells the others that he has Chow’s purse containing eighty thousand dollars worth of Bellagio chips. After their tuxedos are flung to them from a passing Tux Shop van, they pull to the side of the road and change clothes. Later, as Doug and Tracy exchange vows, Doug promises Tracy he will never put her through anything like that again. During the reception, Phil spends time with his family and Stu breaks up with the nagging Melissa. Later in the day, Stu’s digital camera is found in the Mercedes and, realizing it contains photos of events they cannot remember, the men agree to look at the pictures one time together and then delete them.