Emily Middleton (Amy Schumer) is in a clothing store looking for a nice outfit. She is telling a woman about her upcoming trip to Ecuador with her boyfriend. The woman, who is actually just a customer, cuts Emily off and asks for an item in her size, which they don't have. Emily's strict boss Lew (Raven Goodwin) then goes over and criticizes Emily for not working and goofing off too much, leading her to fire Emily.
Emily then meets up with her boyfriend Michael (Randall Park) at a restaurant. As Emily is talking excitedly about their trip, Michael breaks up with her because his band is going on tour and there is more potential for him to meet other women. Emily pitifully tries to spin it around and break up with Michael, but he just leaves her alone as she starts crying.
We meet Emily's mother Linda (Goldie Hawn), who lives with her cats and agoraphobic son Jeffrey (Ike Barinholtz). Linda catches wind of Emily's breakup as she posts about it on Facebook. Linda calls Michael a "son of a bitch" on Emily's wall, which starts an awkward public conversation between mother and daughter.
Emily goes to her mom's house for comfort. She sits down to have dinner with Linda and Jeffrey, the latter bickering with Emily and getting on Linda's nerves. Emily tries to find another friend to join her on her trip, but no one will go. Emily then goes into Linda's closet to look for a shirt and she finds a scrapbook of Linda in her youth going on numerous trips and having the time of her life. Impressed by this revelation, Emily proposes that Linda go on the trip with her. Linda doesn't want to as she prefers to play it safe, but Emily eventually convinces her to go.
The two arrive in Ecuador and stay at a resort. Emily is stuck with Linda in the king suite which was meant for a romantic getaway with Michael, but not anymore. They go outside by the pool where Linda applies a heavy amount of sunscreen to Emily's body. They then meet Ruth (Wanda Sykes), who is on vacation with her mute ex-Special Forces best friend Barb (Joan Cusack). Ruth overhears Emily and Linda's conversation about the dangers out there, which Ruth says are very real, but Barb can get in and out of dangerous situations.
Emily goes to a bar where she meets a handsome stranger named James (Tom Bateman). They hit it off and have drinks. He takes her to a nearby party where everyone is practicing capoeira, and Emily accidentally kicks a guy in the face. Afterwards, Emily and James agree to meet the next morning for a trip. Emily goes home super drunk and invites Linda to go with them. Linda refuses but Emily forces her to go when she rips out the last pages of a book Linda is reading.
The ladies join James for a drive around an unfamiliar and shady area. Linda sees a van drive next to them, and the two men inside put on masks. After Linda comments on it, the van hits their car moments later.
Emily and Linda wake up in a cell. The kidnappers enter and make Emily give up their PIN number, as well as Linda's home number since Jeffrey is the only guy they can count on right now (to Emily's horror). The kidnappers' boss, Hector Morgado (Oscar Jaenada), calls Jeffrey and tells him they are holding his mom and sister for a $100,000 ransom.
The kidnappers haul Emily and Linda away in the trunk of a car. Emily manages to break free of her bonds and undoes the rope around Linda's wrists. They pull on some wires and break out of the trunk. A pick-up truck driver passes by, and the ladies hop on the back. They are promptly chased by one of the kidnappers. Emily pulls Linda onto the truck and grabs a shovel, whacking the kidnapper across the head and killing him.
The truck driver stops somewhere and chastises the women in Spanish for killing Morgado's nephew. They then go to a nearby outdoor bar where they find a phone and a turkey leg (Emily is starving). Emily calls Morgan Russell (Bashir Salahuddin), a federal officer in Washington DC. He instructs Emily to go with Linda to a consulate in Bogota, the capital city of Columbia, leading them to realize they've been smuggled to a different country. The ladies talk to the bartender, who points them out to a guy that can help them - Roger Simmons (Christopher Meloni). He agrees to take the ladies to Bogota.
Jeffrey gets in touch with Morgan himself. Although trying to seek help, Jeffrey asks if they have an A-Team kind of squad to help find his mom and sister. Morgan just hangs up.
Morgado and his goons find Emily and Linda. He calls Emily out for killing his nephew, saying he will kill Linda now. Linda notices a spear gun and tells Emily to threaten them with it while Linda distracts the villains. Emily takes the gun but accidentally pulls the trigger, launching a spear into the throat of Morgado's son. As Morgado cradles his son, Emily and Linda run away with Roger, who helps them escape on his boat.
Roger guides the ladies through the forest. They set up camp for the night, where Roger tells the ladies that he came out there in search of adventure, and that he has roughly a week to live because of cancer, so he's trying to make the most of his time.
Jeffrey continues trying to get help from Morgan. It gets to a point where Jeffrey makes the mistake of mentioning Morgan's wife. Morgan then threatens Jeffrey if he ever calls again, leaving the guy terrified.
In the morning, Emily and Linda follow Roger as they continue walking through the forest. They come across a cliff with a ledge on the other side. Roger tries to swing across on a vine, but it breaks and he falls to his death. Emily and Linda then walk away on their own, which starts an argument about how Linda is always criticizing Emily while Emily is obsessed with letting everyone else know she is having a good time through social media. Emily suddenly passes out.
Emily wakes up in a small village that Linda brought her to. She is being treated by Dr. Armando (Arturo Castro). He tells Emily that her constant hunger and subsequent passing out is the result of a tapeworm in her body. He and his assistant pry Emily's mouth open and dangle meat in her face to lure the tapeworm out. The worm comes out and Armando starts pulling it out. Emily freaks out and runs out, but the worm is pulled out.
Emily starts to interact with the local women and helps them in their chores. Soon, Morgado and his goons arrive and chase after Emily and Linda. They make it to a lift that only fits one person. Linda lets Emily take it so she can reach Bogota, leaving Linda to be taken by Morgado.
Jeffrey shows up at Morgan's office. Morgan immediately knows who it is and calls security. Jeffrey then pleads for help, because if something happens to Emily and Linda, Jeffrey will bother Morgan non-stop.
Emily makes it to the consulate and is told by an embassy worker that arrangements are being made to bring her back to the U.S. But Emily refuses to go without her mother. She finds a phone and gets in touch with Ruth and Barb, who agree to help her out.
Emily finds Ruth and Barb, who have found James and are interrogating him. James apologizes for his involvement in the kidnapping and spills the details to Morgado's whereabouts.
The three sneak into Morgado's compound, but Emily gets separated from Ruth and Barb when they hop on a truck that drives away. Emily manages to find Linda on her own. She tearfully hugs her mom and apologizes for dragging her out there. Linda says it's okay but that they need to get out now.
Emily and Linda escape and find a van to ride away in, but Morgado finds them first. He breaks Emily's window and pulls her out. Emily fights back using her capoeira moves, while Linda uses a dog whistle to summon a dog to attack Morgado. He drops his gun, leaving Emily to hold it at him. Before Emily can do anything else, a team of agents show up and arrest Morgado. Jeffrey and Morgan are with them. Jeffrey runs to Linda while Morgan thanks Emily for helping them catch Morgado. Morgan is also happy to not ever have to deal with Jeffrey again.
One year later, Emily and Linda are taking another vacation in Kuala Lumpur. Emily gets hit on by another guy at the bar, but she says she is there with her mom. He asks why she's there with her, and Emily replies because her mom is "fucking awesome". The guy says that that's sweet...and that Linda's breast is hanging out. Emily runs to help her mom and they dance together.