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Maura Ellis (Amy Poehler) is told by her parents (Dianne Wiest and James Brolin) that they are planning to sell their home in Orlando, and asked to come and clean out the things from her childhood bedroom. Her parents also ask that she tell her sister, Kate (Tina Fey), because she does not take bad news well. Maura, a recently divorced nurse, is constantly trying to help people, and Kate is an unorganized and irresponsible stylist, who is living in her friend's house, while her teenage daughter, Haley (Madison Davenport), lives elsewhere and refuses to tell Kate where she is staying. Maura calls to tell her the news, but stops short of telling Kate that their childhood home is being sold, and instead convinces her to come to Orlando for a while, as Kate has just been kicked out of her apartment. Kate and Maura meet at the airport, and on the drive home, they hit on a man, James (Ike Barinholtz), doing yard work outside of his home. Upon reaching their childhood home, they discover the house has already sold, and their parents have already packed up and sold all of the family's belongings, except for the things in the sisters' room. Furious, Maura and Kate find their parents at a retirement community and confront them. The sisters are told that the deal is done and that they need to be out of the house by the end of the weekend with everything completely moved out. As they are going to sleep, Kate convinces Maura to have one last party in their childhood home.
The next morning, the sisters are awoken by the new homeowners coming to see the house in order to begin to plan all of the things they want to change when to move in, and tell them that the home needs to be in perfect condition in order for the sale to go through, causing great distress to Maura and Kate. Moving forward with their plans to host a party, Kate and Maura go through and invite most of their friends from high school, excluding Brinda (Maya Rudolph) whom Kate hates. The sisters go shopping in order to prepare for the night. While shopping for decorations, they have a run-in with Brinda, who is upset about not being invited. The sisters then go to a nail salon, where Maura invites her nail stylist to the party, and tries to convince Kate to apply for a job there. Kate speaks to the owner and he refuses. Kate convinces him to pretend to give her a job so that Maura will think that she is taking responsibility. While shopping for dresses, Haley calls Kate to check in with her. Kate hands the phone to Maura, whose conversation with Haley reveals that Maura has been housing Haley for the past several months, unbeknownst to Kate. Maura convinces Haley that Kate has changed for the better, and Haley buys a plane ticket to Orlando to surprise Kate. The sisters finish up their shopping, and stop by James' house where Kate forces Maura to ask him to come to their party, and he agrees. While preparing for their guests to arrive, Maura asks Kate to remain sober for the party, so that she will be able to enjoy the party. Kate reluctantly agrees.
As the party begins, the sisters realize that all of their high school classmates have matured and do not want a wild party. To prevent the guests from leaving, they give a speech to their guests and ask Dave to invite his drug dealer over so they can buy marijuana. More of their friends show up, including their nail stylists, who are able to turn the party around into the epic celebration they were hoping for. Brinda arrives uninvited, where she is promptly kicked out by Kate. James also arrives, and he and Maura try to start a conversation together, but keep getting interrupted by the party guests. As revenge, Brinda calls in a noise complaint to the police, though Kate and Maura are able to flirt and talk their way out of trouble. As the night progresses, the guests become more and more out of control. Brinda, after failing to stop the party, takes revenge by adding blue paint to the water system for the pool and sprinklers. Haley calls her mom to surprise her about being in town, when she learns that her mom is at a party. Haley lashes out at her mother for continuing to be irresponsible, refusing to believe that Kate is sober. Kate decides to drink since Haley already suspects she is drinking. With Kate no longer watching over, the party continues to become increasingly destructive. Brinda again sneaks in, but this time, she and Kate are able to resolve their conflicts and she is allowed to stay. Meanwhile, Maura has snuck off with James, hoping to having sex with him, but things keep going awry, with Maura falling through the ceiling, and James landing on her childhood ballerina music box. James leaves the party with the music box up his anus. Kate learns from her parents that they were planning to give her a portion of the money they receive from selling the house, so that she can get set up in her new life. Kate realizes that the house will no longer sell because of the destruction and tries to end the party early. She calls the police to complain about the noise, but the responding officer realizes that Maura had helped his cousin in high school, and declines to shut it down.
After failing to have sex with James, Maura leaves her room and is horrified to see the mess that the party made. Maura learns that Kate has gotten drunk, despite promising to not have alcohol, and becomes furious with her. At the same time, Kate learns that Maura has been housing Haley, and is incensed. The sisters find each other and begin to fight. Haley and her grandparents show up at the party and are horrified by what they see. The backyard pool becomes a sinkhole, and Haley falls in. Kate comes to her rescue and helps her get out when Haley refuses to climb a ladder. Once the parents kick the guests out, they tell Kate and Maura that they are tired of taking care of both of them, and that they need to get their lives together.
The next morning, the sisters are woken by their parents so that they can begin the process of cleaning up after the party. Maura offers to help pay for the house, so that her parents will not have an issue with selling, but they refuse, as they believe that Maura needs to stop helping since she is often unhelpful. Kate tells her parents that she does not have a home, and would like to live in the house. They refuse this as well, saying that she can stay for the next ten days while she repairs the house. Kate enlists the help of James to help repair the damage. Maura and Kate apologize to each other, and Kate convinces Maura to try and connect with James. Kate fixes up the house, and they are able to sell it with the help of Brinda. Kate opens a new nail salon in Orlando, and Maura and James have moved forward and are now in a relationship.
The movie closes with Kate and Maura celebrating their first Christmas at their parents' new home with all of the family happy together.