The film opens during a college Halloween party in 2006. Best friends Jess (Scarlett Johansson) and Alice (Jillian Bell) are playing beer pong while their friends Blair (Zoe Kravitz) and Frankie (Ilana Glazer) cheer them on. Jess and Alice have one cup left to hit, and Alice is nervous. Jess encourages her friend to win, and Alice shoots the ball from her mouth into the cup. Everyone cheers. Alice carries Jess on her back until Jess hits her head on the doorway and falls. Afterwards, the four ladies go to Jess and Alice's room to talk about Jess going to study abroad the following semester. They vow to stay friends forever. Then one of their schoolmates drunkenly walks into the room and starts peeing on the floor.
Ten years later.
Jess is living in Washington DC and currently running for a state senator position. Her campaign managers think she comes off kind of uptight in her ads and suggest that she loosen up. Jess is also engaged to a guy named Peter (Paul W. Downs). Alice, who is now a teacher and living somewhere else, keeps trying to get in touch with Jess for an upcoming bachelorette party they have planned. Jess just wants to spend some alone time with Peter, but he tells her it's okay to take Alice's calls.
Peter drives Jess to the airport to meet with Alice so they can head to Miami for the party. Alice is excited so they can be "swimming in dicks." When they get to Miami, they meet up with Blair (now a New York City lawyer going through a custody battle with her ex-husband for their three-year-old son) and Frankie (now a jobless activist), both of whom still have a bit of a thing going on since their brief romantic relationship in college. The ladies get together, and Alice pulls out a bottle of champagne. Frankie pops it open, but the loud noise freaks everyone in the airport out.
The ladies arrive at their beach house that they rented for the weekend. They meet their neighbors, Pietro (Ty Burrell) and Lea (Demi Moore), both of whom are very sexually active swingers and are particularly attracted to Blair.
That night, the ladies go out to dinner. Jess wants to call it an early night but her friends are devoted to giving her the time of her life. Jess invites her Australian friend Pippa (Kate McKinnon) to join them, making Alice clearly jealous. Frankie gets up to go to the bathroom and comes back with some cocaine, getting her friends to join her for some bumps.
The friends continue their night on the town by heading to a nightclub. Alice gets wasted and starts puking. Then the ladies enter a talent competition doing a performance from when they were in college, but it gets ruined when Alice goes for a trust fall and nobody catches her. While dancing, Blair suggests to the others that they get Jess a stripper.
The five friends get back home to the beach house and all of them continue doing drugs (smoking pot and snorting cocaine). The stripper, Jay (Scott Cooper), shows up. After using the bathroom, he begins to striptease for Jess. She's enjoying it until he calls her a slut. Alice then wants in on the action, so she jumps on Jay, accidentally knocking him over and causing him to hit his head on the edge of the fireplace. His head starts bleeding and the ladies freak out. Despite their efforts to help him, Jay is dead. Everyone panics since the house is made of glass and people can see them. The pizza man shows up, so Pippa answers the door to cover things up while the others try moving the body.
Meanwhile, Peter is hanging out with his buddies for a wine-tasting session when he decides to call Jess. Jess is too nervous to talk and she blabs that something went wrong with a stripper/prostitute (Frankie says she got him off Craigslist). When Peter asks if she still wants to get married, Jess freaks out again when Frankie takes her phone and smashes it. Peter is left thinking Jess is cheating on him. At the behest of his friends, he is inspired to drive all the way down to Miami and win her back. He makes a stop at a convenience store for adult diapers and energy drinks.
The ladies continue trying to hide the body. Frankie and Blair leave briefly to purchase a cell burner phone, leaving the other three with a dog running up to the house in front of Jay's body. Pippa tries to send the dog away before his owner appears, and she gets her left wrist bitten. They try moving the body to the garage, but the door malfunctions and the cab bringing Frankie and Blair back almost catches them. The friends realize they have no choice but to hide the body in the closet on a sex swing.
Blair calls her Uncle Jack (Peter Francis James) to ask for advice. Jack says that they all could be charged for involuntary manslaughter, but with lack of evidence, they wouldn't have a case. Then he mentions that they shouldn't touch the body, but Pippa admits they already moved him. Jack says this could mean up to 15 years in prison, but then he tells the ladies if there's no body, then there's no case.
The ladies contemplate chopping up the body, but they can't go through with it. They decide to take a jet ski to go out and dump Jay's corpse into the ocean. Before they can do it, Pietro and Lea come outside under the assumption that the ladies are going skinny-dipping. Pippa has to pretend to make out with Jay to avoid suspicion. The couple leaves, so the ladies say some final words for Jay before Pippa rides the jet ski far enough to dump the body. She then rides it back to the shore so fast that she flies off it and lands on her neck, but she's fine. However, Alice sees that the couple has a security camera that has possibly recorded them dumping the body. They all look at Blair for the next part of their plan.
Blair reluctantly talks Pietro and Lea into sex outside by the beach so that they can have it filmed by the security cameras. After a very passionate session (off-camera), Blair asks for the tape, but the couple says that the cameras don't work since they don't pay for the service. Blair is pissed at her friends for making her go through with that, but they are just glad they are safe. They proceed to clean up all the blood in the living room.
Meanwhile, Peter continues his road trip up to Miami in his diaper and hopped up on energy drinks and expired Russian speed pills. He gets pulled over by a cop for speeding, but he lets him go with a ticket. Peter then stops to get gas but his card is declined. He puts together money by encountering two separate weird guys after washing their cars. The first guy offers Peter meth and asks for a blowjob, but Peter refuses. The second guy wants to blow Peter and asks for meth, so Peter introduces the two guys and gets his gas money.
At the beach house, Alice wants to do a "Human Friendtipede" photo outside. When they look at the picture, they see that Jay's body has washed up on the shore. They put Jay back on the sex swing, and they all hear a loud knocking at the door from someone claiming to be a cop. Frankie answers the door while the others hide. The cop, Scotty (Colton Haynes), enters and tells Frankie to get up against the wall. Scotty starts to frisk her, and Frankie headbutts him, knocking him out cold. The ladies try to pick Scotty up, but they rip off his uniform, meaning HE was the real stripper, but now they don't know who Jay was.
The ladies bring Scotty upstairs to rest. Everyone is tense and still freaking out, leading to a big argument. Frankie and Blair go at it while Pippa calls Alice out for her behavior toward her all evening. Blair then lets it slip that Jess had a bridal shower that Alice wasn't invited to. Jess then admits to Alice that she is always making Jess spend time with her and making her feel guilty for not doing so, and that the bachelorette party was mostly for Alice to prove that her life doesn't suck. Alice is hurt, and Jess goes upstairs to calm herself down.
Moments later, another knock is heard at the door. Two guys, Frazier (Dean Winters) and Ruiz (Enrique Murciano), claim to be detectives and ask for Jay. Alice answers the door and admits that Jay is dead. They show the guys Jay's body in the closet. Frazier says this was self-defense, so the ladies are off the hook. They cheer the fact that they are safe. Frazier then asks the ladies about diamonds that Jay stole and is hiding. Pippa then sees on the TV that police are looking for Jay, Frazier, and Ruiz, who are all diamond thieves. Although Pippa tries to alert the other ladies, the guys hear the news report and hold the ladies hostage, plus Scotty when he wakes up and starts screaming.
Jess finds a card from Alice that says how much their friendship means to Alice because Jess was her first true friend when they were in school. Jess then hears the commotion downstairs. Frazier goes up and gets sprayed in the face with hairspray. Jess gets his gun and forces him to handcuff himself to the sink while she goes to save her friends. She aims her gun at Ruiz, who has everyone tied up together. Before she can pull the trigger, Ruiz moves and Jess has it aimed at Alice. She stops herself quickly and instead leaps off the balcony to tackle Ruiz. While she fights him, the others grab Ruiz's gun, and Alice shoots him in the leg before Jess bludgeons him with a statue. Jess goes to help her friends, but Frazier uncuffed himself since the keys were attached to the cuffs. He prepares to kill them until Peter drives through the front of the house, slamming into Frazier and killing him. Jess goes over to Peter, who still thinks Jess was cheating. She clarifies things and says she still wants to get married, and even suggests that they do it immediately.
The next day, Jess and Peter are married at a foam party that Alice got tickets to, with Pippa officiating. The friends all enjoy the party, with Frankie and Blair getting back together, and Alice going to hook up with Scotty. Jess then gets a call from one of the campaign managers who tells her that the story of her and her friends taking out the diamond thieves is big news, bringing in lots of sponsors and volunteers, inspiring confidence in Jess's election. She is asked to come back to start interviews, but she chooses to stay to enjoy time with Peter and her friends.
During the credits, we see that Jess has officially been elected state senator. Pippa goes up to perform a song with painfully obvious lyrics about them killing a guy.
After the credits, Jess and Peter take Alice home from the party. Alice goes to make herself some penis pasta, and she discovers the stolen diamonds which were hidden in that pasta box the whole time.