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 North Korean beauty products. 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. The girls are taken to the local Sheraton 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.
The following day, Meg suggests they go on a hot air balloon ride, knowing Kate is scared of heights. Kate attempts to hide her fear of heights and goes on the balloon ride with Meg and Ryan, but she eventually caves in, though Ryan gives his attention to her to keep her calm much to Meg's chagrin. The ride eventually ends early when Meg accidentally pops a champagne cork into the only eye of the one-eyed pilot. Later, at the hotel pool, Kate and Meg get into a diving competition to impress Ryan, which ends when Meg injures her eye with a risky flip.
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 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 classes and is in a long distance relationship with Craig. It is shown that Meg moved into an apartment only a few doors down from Kate so the two can still be close.Alexandra Daddario as Kate, a school teacher and Meg’s best friendKate Upton as Meg, a business woman and Kate’s best friendMatt Barr as Ryan, a young man for whose affection the girls ruthlessly competeMatt L. Jones as CraigRob Corddry as Principal Moss, Kate’s nemesisKal Penn as Anuj, a hotel managerMolly Shannon as NancyCarrie Genzel as Harold's BuyerWilliam H. Macy
On March 25, 2015, it was announced that William H. Macy would direct and star in a road-trip sex comedy film, titled The Layover, scripted by David Hornsby and Lance Krall. Keith Kjarval would produce through Unified Pictures, along with Aaron L. Gilbert through Bron Studios. Lea Michele and Kate Upton were cast to play the best friends who decide to take a vacation to avoid their problems. Matters become even worse when both find themselves falling for the same guy during an extended layover in St. Louis. On April 24, 2015, TheWrap revealed that Alexandra Daddario joined the film. Rob Corddry, Kal Penn and Matt Barr were confirmed for the cast on May 7, 2015, by THR. Later reports confirmed the casting of Daddario as Michele's replacement after she left the project, while Matt L. Jones was also confirmed.
Filming began in the first week of May 2015 and wrapped in the second week of June 2015.
On April 11, 2017, it was reported that the film would debut on DirecTV Cinema on August 3, 2017, followed by a limited release through Vertical Entertainment on September 1, 2017.
Review aggregation website Rotten Tomatoes gives the film an approval rating of 0%, based on reviews from 16 critics, with an average rating of 1.9/10.
Richard Roeper writing for The Chicago Sun-Times compared the movie to the unpleasantness of enduring a layover at O'Hare International Airport and expresses surprise that someone as great as William H. Macy could be responsible for directing "an unholy mess".