The movie opens with Phil (Bradley Cooper) on the phone in the middle of the desert. He is calling the fiancee of his best friend Doug (Justin Bartha) and tells her that they messed up. "We lost Doug." The fiancée, Tracy Garner (Sasha Barrese), freaks out because she and Doug are supposed to get married in 5 hours. "That's not going to happen."
Two days earlier, Doug and his soon-to-be brother-in-law Alan (Zach Galifianakis) are trying on tuxedos. Alan says it's OK if Doug doesn't bring him to the bachelor party tonight. Alan is severely socially inept but Doug makes it clear that he wants Alan to be there with him. Since they are going to be brothers soon, they have to look out for each other.
Doug goes to talk to his future father-in-law, Sid Garner (Jeffery Tambor), and is given permission to take his Mercedes to Vegas for the bachelor party since Sid remembers what it was like to be a young man. Doug thanks him and promises that he will be the only one to drive the car that day. Doug and Alan then leave to pick up the others.
Doug's best friend Phil is a high school teacher reminding one of his classes to pay 90 dollars for a field trip to an observatory, which they all promptly pay. Phil then removes the $3500 from their envelopes and puts them into an envelope marked Vegas. He grabs his bag, ignores a student and jumps into the Mercedes. The group then goes to get their last member.
Stu (Ed Helms), a dentist, is at home arguing with his girlfriend, Melissa (Rachael Harris), about the bachelor party. Stu tells her that they are going to Napa Valley for a wine tasting. Melissa is convinced, however, that Phil will find a way to find a strip club. Melissa treats Stu very badly, but Stu takes it with a smile and tries to kiss her but she won't have any of it. The guys arrive and Stu leaves with them.
The group drives to Las Vegas and check into Caesars Palace. They try to decide how to pay and Phil volunteers Stu's credit card as the main payment method. Stu flatly refuses, telling Phil that Melissa would see the charges and realize that they went to Vegas. Doug tells Stu that they'll sort out the payment when they check out. They go upstairs to get ready for their 1st night out. Stu tells Doug and Phil that he's going to propose to Melissa and use his grandmother's Holocaust ring as an engagement ring. While Doug congratulates Stu, Phil openly points out that Melissa is a controlling bitch. Stu and Phil get into an argument and Phil tells Stu that Melissa is clearly not a good person since she cheated on Stu when she slept with a bartender on a cruise. At that point, Alan comes in with a satchel and asks the guys if they're ready to let the dogs out.
The four go to the roof and make a toast. Alan treats everyone to a shot of Jägermeister and then reads an awkward speech to the group telling them how the four of them are like a pack of wolves. Phil then tells the others that he's toasting them to a night they will never forget.
Time passes as we see the night skyline of Las Vegas change slowly into the next morning.
A woman walks out of the room carrying her stiletto heels. Stu comes to on the floor with blood on his shirt. Phil is sleeping on the floor and Alan wakes up on the couch. The room is a complete mess. A chair is horribly burned, statues litter the room, and there are a bunch of champagne bottles aligned as bowling pins. Alan goes to the bathroom and sees a live tiger. Phil wakes up when Alan steps on him and thinks that Alan is imagining things. He laughs at the fact that there is a tiger in the bathroom and tells Stu that his head hurts. Stu realizes that he's missing a tooth and Phil can't help but laugh. He stops once they realize Doug is nowhere to be found. They also note that Doug's mattress is missing. During their search, they hear a baby crying in the closet. They don't know whose baby it is but decide to take it with them to breakfast.
At breakfast, Alan makes the baby pretend-masturbate for the guys and lovingly dubs him "Carlos." Phil, Stu and Alan realize that they can't remember anything from the night before. They check their pockets for clues to what happened last night. Alan has Stu's tooth, Stu has a receipt for an $800 withdrawal at the Bellagio, and Phil has a hospital bracelet on his wrist. They decide to make the hospital their first stop.
Outside the hotel, the trio waits for the valet to bring around their car. They notice a cleaning crew removing a mattress impaled on Caesar's statue on an upper level of the hotel. Phil notes that they must have had a wild night. The valet drives up, not in the Mercedes, but in a police car and gives Phil the keys. They drive off and head to the hospital to get a lead on where Doug is.
The ER doctor tells them that Phil was admitted with a mild concussion and that Doug was with them when they visited. Phil bribes him for more information and the doctor tells him that they had just come from a wedding at a chapel a few blocks away. The doctor also tells Phil that he had high traces of "ruphylin" (referring to the date-rape drug known as "roofies") in his system. Phil freaks out at the possibility of having been raped, but the doctor tells him he wasn't. The trio decides to head there.
When they arrive at the chapel, they are greeted like family by the proprietor, Eddy. They can't remember why, but soon found out that Stu married a woman named Jade (Heather Graham) the night before and that everyone was present for the wedding. Stu freaks out a little, Phil looks into an annulment and Eddy gives them Jade's address.
The trio head to the car and as they pull out, they are confronted by a pair of Asian gangsters demanding that the trio return someone they kidnapped. The gangsters pull out guns and threaten the trio before accidentally shooting Eddy in the shoulder. Phil drives the car out of the lot. They get to Jade's and find her on the phone freaking out because she couldn't find her baby, who turns out to be named Tyler. She sees Stu and is happy to see him but he freaks when he finds out that she's a stripper who works as an escort and he gave her his grandmother's Holocaust ring. The group is interrupted by the arrival of two police officers who arrest the trio for stealing their car.
At the police station, Phil decides to call Tracy and tells her that they are enjoying Vegas so much they are staying an extra day. He doesn't tell her that they lost Doug and is forced to hang up when they are taken to the interrogation room. The two officers are angry that the trio stole their car and want to hold them over to be arraigned the following Monday. Phil explains the situation and then attempts to blackmail them into a deal (for losing track of their squad car), which backfires. The officers agree to let the guys off the hook but trick all three into being test subjects for a group of kids, demonstrating the effects of a Taser. The guys agree and weather the effects of being shocked by both the police and a couple of the kids, one of which is determined to get revenge on Alan when Alan kicked him lightly in the squad room.
After the demonstration, the trio head over to recover the Mercedes that the police impounded. Stu is surprised that the car is in pristine condition and they then drive back toward the hotel to see if Doug went back. On the way they hear a knocking in the trunk and think that Doug is in the trunk of the car. They open it only to have a flamboyant and naked Asian man named Leslie Chow (Ken Jeong) jump out with a crowbar and attack them. After he runs off naked, Alan admits that he spiked their Jägermeister with the roofies, thinking they were Ecstasy pills. Stu flips out, but Phil plays it cool and the trio returns to the hotel.
They are about to enter the hotel room when they remember the tiger. They cautiously open the door to find Mike Tyson and his bodyguard in the room. Tyson is singing "In the Air Tonight" by Phil Collins, getting the guys to join in before knocking Alan out cold. It turns out the tiger belonged to Tyson and the reason they were able to find the hotel room was because they found Doug's jacket and room key in the tiger cage. The trio are terrified because Tyson implies that the tiger may have eaten Doug. Tyson gives them an hour to bring the tiger back to his house. Alan puts five roofies into a raw steak in order to knock out the tiger, and two hours later they cart the tiger into the Mercedes.
While driving to Tyson's mansion, the tiger wakes up and scratches Phil's neck. The trio gets out of the car and pushes it the last mile of the way while the tiger chews up the interior of the car. Upon arriving at the mansion, Tyson shows them a security tape of them stealing the tiger and Alan urinating into Tyson's grotto pond. Doug was with them and they put it into a police car but not before Phil screamed, "Look, I'm raping Tyson's tiger" and pantomiming having sex with the animal. Tyson asks where they got the cop car, and gives them props when they tell him they stole it. With no further leads, the group heads back to the hotel.
On the way to the hotel, Chow and his men crash their car into the Mercedes and force it into a pole. They tell Phil that he kidnapped Chow, calling him "my lucky charm" and that he wanted to take Chow home with them. The gangsters also noticed that Alan took Chow's purse (which resembles Alan's satchel) with him and that the satchel Chow carried had $80,000 worth of Bellagio casino chips. Phil says they'll return the money, and Chow gives them until sunrise to get it to them and shows them that he has Doug in his SUV with a hood over his face.
The gang returns to the hotel and can't find the satchel. They call Jade and let Alan try counting cards in order to win back the $80,000. Alan is a success and they make over $82,000. Just as the security men are about to move in on them for card counting, Jade fakes an accident and Alan and Phil get away. The group drives to the meeting point to make the exchange. They give Chow $80,000 in cash and Chow gives them Doug. Unfortunately, it's the wrong Doug. The Doug that Chow's gangster kidnapped (Mike Epps), who is African American, turns out to be the man who sold Alan the bad Ecstasy. Phil gets mad and tells Chow to give them back their money and to take "Black Doug" with him. Chow refuses and drives away.
Phil decides that it is time to end the charade and tell Tracy what happened. We hear the opening play in the background as Black Doug, Stu and Alan discuss the reasoning behind the name roofies. Stu then realizes that they put Doug on the roof of Caesars Palace as a joke but forgot him and locked him up there. The mattress on the statue of Caesar was thrown there by Doug while trying to signal for help. Stu immediately tackles Phil and takes the phone away from him. He tells Tracy that Phil is drunk and that they are heading back now with Doug.
The trio race to the hotel and find Doug sunburned and huddling for shade on the roof. Doug attacks Phil when Phil tells him that he is going to miss his own wedding. The group checks out and races to the now ruined Mercedes. Stu and Jade have a heart-to-heart talk and Jade tells him she knows the marriage was a mistake and gives him back his ring. Stu asks her if she wants to go on a date next weekend and she agrees. She also tells him that the reason Stu is missing a tooth is because Alan told him that he wasn't a good enough dentist if he couldn't remove his own tooth. Doug pulls out the missing satchel with Chow's $80,000 in casino chips. It had been left with him on the roof.
Phil speeds down the highway on the way to the wedding. A tuxedo shop van drives up and tosses them four tuxedos that they ordered via phone. The group arrive at the wedding a few minutes late. Tracy walks down the aisle with Sid and asks Doug what happened. He explains what happened and tells her it will never happen again as long as they are married. Tracy forgives him and the two get married.
Phil is happy to see his wife and son at the reception and spends the evening happy to be home. Alan and Stu are drinking at the bar when Melissa shows up. Melissa is mad that Stu didn't call at all and ignored her calls. She flips out when she sees he's missing a tooth. Stu finally can't take it anymore and flips out on her. She asks him when their relationship stopped working and Stu loudly announces that it was over when she had sex with the sailor on the cruise. Phil smiles proudly while Doug and Tracy look on in shock. Alan corrects him by saying it was a bartender, and Stu laughs. He tells Alan that they should go dance, which they do. Afterwards, Alan hits on Melissa and gets shot down.
The guys are all gathered on the patio when Alan walks up with Stu's camera he found lodged in the backseat of the car; it contains photos of their adventures and mishaps in Las Vegas. They decide to look at the photos once and then delete the evidence.
During the credits, the pictures are shown:
* A bunch of photos with Phil, Doug, Alan and Stu hanging out with strippers * Stu and Jade hooking up at the strip club. * Chow, Alan and Phil gambling * Phil and Doug doing cocaine with Carrot Top * Doug posing in front of Tyson's mansion with the stolen police car and the officer's shotgun * Tyson asleep next to a blonde * Alan asleep next to Tyson and a blonde * Alan firing a shotgun at the statue at Caesars Palace * Doug asleep on the roof * Alan pretending to rape Doug * Alan getting a blow job from a hotel maid * Stu and Jade's wedding * Stu ripping his tooth out of his mouth with pliers and the aftermath * The guys together before the night began.