Kate (Alexandra Daddario) and Meg (Kate Upton) are childhood friends and roommates in Seattle going through stressful times. Kate is a high school English teacher, bored of her regular curriculum and under pressure to quit by Principal Moss (Rob Corddry) who believes she should be in a different profession. Meg is a cosmetics saleswoman trying and failing to sell beauty products... illegally imported from North Korea. After a night of drinking away their stress, the adventurous Meg suggests they go on vacation to get their groove back. The reserved Kate is reluctant, but ultimately acquiesces as Meg had already booked non-refundable tickets to Fort Lauderdale using Kate's frequent flyer miles.
Barely making it to their flight on time, Kate is put in a window seat and Meg gets an aisle seat. The middle seat is eventually occupied by Ryan (Matt Barr), a handsome firefighter on his way to a wedding. Both Kate and Meg are immediately attracted to him and begin to shamelessly flirt with him, but Kate eventually passes out having taken too many anti-anxiety pills. A few hours into the flight, the plane is diverted to St. Louis due to a hurricane warning in the Florida area. The girls are taken to the local Sheraton Hotel and bump into Ryan, who invites them to drinks and the hotel club. When Ryan learns the hurricane will delay his trip even further, the girls attempt to cheer him up with a dance competition. Before going to bed, Kate tells Meg that she will fight her for Ryan's affections.
Their following day is unfortunate when during their ride in a hot air balloon, Kate is having a panic attack due to fear of heights and Meg accidentally pops a champagne cork into the only eye of the one-eyed pilot; and Meg ends up injuring her eye after a risky flip into the swimming pool.
When it is learned the hurricane will move away from Florida, Ryan is able to get a ride from Craig (Matt Jones), a jewelry salesman who had taken a liking to Meg but had been continually rebuffed by her, and the girls ask to tag along. Kate shows embarrassing childhood photos of Meg to the guys for their amusement and in response, Meg locks Kate in a messy gas station bathroom, forcing Kate to escape through a high window covered in feces.
Back in the car, Kate fakes an injury to get a massage from Ryan, prompting Meg to put sleeping pills into a bottle of wine to give to Kate. When Kate declines to drink, Craig, who is driving, takes it instead, much to Meg's horror. After a few hours, Craig eventually passes out and crashes the car, forcing the four to spend the night at a motel.
When Kate sees the pills in the bottle, she asks for a hotel room for herself. Meg says that she can have Ryan, but Kate proclaims she never wanted Ryan, just that she didn't want Meg to have him. Meg decides to go to a local bar where Craig joins her. When Craig fails to impress Meg, he suggests to her that she should be open to the qualities of other guys.
Back at the hotel, Ryan makes a pass at Kate, who gives in and has rigorous sex with him. In the morning at breakfast, Meg tells Kate they should stop ruining their friendship over a guy, but when Meg lets slip that Ryan has a misshaped penis, something Kate had seen from having sex with him, Kate realizes Meg had sex with Ryan as well and reaches breaking point with her, with the two getting into a physical fight over their issues with each other, Meg's selfishness and Kate's unwillingness to take chances, making a mess of the motel lobby in the process. Their fight ends when the motel manager calls the police on them.
Craig reveals to the police that Ryan had taken his car to reach the wedding on time. When he looks up Ryan's Google Plus profile, he sees that Ryan is the one getting married and reveals this to the girls. Appalled, the girls beg to be let go to stop the wedding and offer to pay for the damages to the lobby.
When they reach the hotel in Fort Lauderdale where the wedding is taking place, they find they were too late to stop it. The girls confront Ryan, who calls them out on throwing themselves at him. The girls still claim it was wrong for him to sleep with both of them the night before his wedding and not telling them he was the one getting married. Ryan admits he had been with his now-wife Genevieve since freshman year of college and hasn't been able to get with anyone else. When the girls meet Genevieve, they see that she is controlling and demanding of Ryan, and decide not to tell her about his actions, feeling Ryan will suffer enough in his marriage.
With a few hours before their flight back to Seattle, Meg tracks down Craig at his jewelry shop to apologize for brushing him off, kissing him before she leaves. At the airport, Meg tells Kate that they shouldn't live together anymore, to which Kate tearfully agrees, as they have been too dependent on each other.
Kate returns to her teaching job with renewed vigor and requests Principal Moss that her students be allowed to indulge their creativity more instead of just following the standard curriculum, and Moss offers her the assistant volleyball coach position. Meg starts taking college classes and is in a long distance relationship with Craig. In the final scene, it is shown that Meg moved into an apartment only a few doors down from Kate so the two can still be close.