The film starts with Mac (Seth Rogen) and Kelly Radner (Rose Byrne) trying to have sex. Kelly starts feeling nauseous and burps a lot before finally throwing up on Mac's face. She then announces that she might be pregnant.
The Radners are trying to sell their home with the arrival of another baby. A couple, the Baiers' (Sam Richardson and Abbi Jacobson) are looking to buy, but the realtor (Liz Cackowski) tells Mac and Kelly that their house is in escrow for 30 days, so the Baiers' will check in every now and then to make sure everything is going okay. Little Stella (Elise and Zoey Vargas) then enters with one of Kelly's dildos.
At work, Mac has lunch with Jimmy (Ike Barinholtz). Like the Radners, Jimmy and his once-again wife Paula (Carla Gallo) are expecting a baby. Mac is a little nervous about having another kid, but he thinks he'll do a fine job as he and Kelly have done well with Stella.
Somewhere on campus, a group of freshmen girls are gathered at a meeting for the sorority Phi Lamda. One girl, Shelby (Chloe Grace Moretz), sparks up a joint as the president (Selena Gomez) is speaking. She tells Shelby to put out the joint and says that sororities can't throw parties, so they just attend frat parties.
That night, Shelby meets two other freshmen, Beth (Kiersey Clemons) and Nora (Beanie Feldstein). They attend a frat party, but they're all disgusted by the sexist and perverse nature of the party. They go back to their dorm to pass a joint, which is Nora's first time doing drugs. She immediately falls in love with them. The RA enters and scolds the girls for smoking weed. Shelby then stands up and says it's unfair that they have to subject to a misogynistic system and to be told what to do by men. They decide to create their own sorority, Kappa Nu.
We catch up with Teddy Sanders (Zac Efron) at a dinner with his old frat brothers Pete (Dave Franco), Scoonie (Christopher Mintz-Plasse), and Garf (Jerrod Carmichael). Since graduating, Scoonie has launched his own app, and Garf became a cop. Teddy hasn't been able to get a good job since his antics as a frat boy led to him getting a criminal record (which he blames on the Radners). Pete's boyfriend Darren (John Early) then proposes to him, and Pete accepts. After the excitement, Pete asks Teddy to move out now that he's engaged. Teddy agrees, hiding his heartbreak.
The girls meet with another realtor (Billy Eichner) to buy the house next to the Radners. However, it's way too much for them to afford. Teddy then appears from the darkened living room with a plan for the girls. He tells them to take their money and put it on the down payment, and he will help them earn the money needed to pay for the house, which he says would equal about five buckets of money for a month's rent. The girls agree.
Soon, the girls move in and throw their first party. Mac and Kelly walk over to meet their new neighbors, horrified to learn they are a sorority. The two ask Shelby to try and keep it down for the next month until they can move and be out of their hair, but Teddy appears and tells the Radners he's in cahoots with the sorority, meaning they'll have more trouble keeping the buyers from pulling out.
Teddy gets his stuff out of Pete's apartment, leading him to snap at Pete when he calls him out on not having much to fall back on since they left their frat, as well as for never knowing that Pete was gay until recently.
Mac and Kelly call Shelby's dad (Kelsey Grammer) to deal with her. She insists that she is trying to be independent and standing up against the sexist system, which is enough for her dad to lay off her. Shelby, Beth, and Nora then declare war against the Radners for snitching on them.
The sorority begins pranking the Radners. All the girls lay on their front lawn and then harass Mac as he gets in his car, while Kelly sprays them with a hose (making them sexier, according to Mac), and then they later throw used tampons at their window. They also throw loud parties and even cry out loud when they have a viewing party for "The Fault in Our Stars". Mac and Kelly report them to Dean Gladstone (Lisa Kudrow), but she can't do anything because they are an independent sorority. Mac gets Jimmy to help him retaliate by getting bugs and infecting the whole house, forcing the girls to pay for an exterminator to fumigate the house.
With only two money buckets, the girls know they need money fast. They know that the school's tailgate is that weekend, and they can sell weed to the students. Teddy expresses his displeasure with the scheme (and the tampon prank), saying they're making the same mistakes he made. The girls all text each other and vote Teddy out of the house. After he leaves, Shelby calls the cops to take out the other weed dealers on campus. This leads to Garf and Officer Watkins (Hannibal Buress) to go on an arresting spree.
Teddy decides to join forces with the Radners (plus Jimmy and Paula) to take down the sorority. They all go to the tailgate event to steal the weed. Teddy distracts the girls by dancing onstage without his shirt while Mac runs around stealing the weed in a garbage bag. Teddy loses attention when he decides to whip it out, and Shelby sees Mac taking the weed. Mac runs for it and switches bags with Jimmy.
The girls' next move involves Shelby and Beth switching Mac and Kelly's phones with their own. They get Kelly to think Mac is somewhere that only Jimmy knows, so she and Paula interrogate him at work. Mac ends up being led to Sydney, Australia because of the girls. When he gets back, Mac and Kelly find that they've been robbed and the sorority is selling their stuff and spray-painted "Kappa Nu" on the house. This causes the Baiers' to pull out from the deal. The Radners then freak out and think they've done a bad job with themselves and as parents to Stella.
The girls find an eviction notice on their door. With barely any money to support themselves, Shelby says the only way they can win is to abandon their morals and resort to having a basic frat party with more sex appeal. They advertise the party to everyone on campus, leading to more people showing up at the house. Mac, Kelly, Jimmy, Paula, and Teddy watch and then plan to shut the whole thing down.
Jimmy and Paula sneak into the party while Teddy tries to shut out the power. Teddy gets into the electrical box, but the girls have a backup power source (pledges dressed as Minions pedaling on bikes). Jimmy ends up getting roofied after drinking the punch (so does Nora). Shelby runs to the Radner house to take their phone so they can't call the cops, but she gets yanked back since she didn't expect the cord. She bites it off and runs away. Mac and Teddy chase her to the garage, but Shelby locks them in there. They try to break the doors down but can't. They resolve to break out using the power of the airbags from an old car. Teddy goes first and he hits the ceiling hard. Mac then jumps and breaks the door down.
The girls then realize they hate the way the party is going since the frat boys are being crude and perverted. Beth and Nora decide to quit the sorority and blame Shelby for the disaster, leading the other girls to leave as well. Mac and Kelly watch, thinking they've won. Shelby stops them and says she only started this to have friends, unlike in high school when she had no one. The other girls cry and bemoan not having their new friends anymore, making Mac and Kelly start to feel sorry for them. Kelly encourages the girls to go back to what they believed in before they sold out. The girls then kick the frat boys out and have a normal party. This attracts all of the Phi Lamda girls, who want to pledge for Kappa Nu. By the end of the night, the girls make enough money not only to keep their house, but to give back to Mac and Kelly so they can buy the house due to overflowing pledges. Mac and Kelly happily agree, as long as they get five buckets of money per month. Meanwhile, Paula is going into labor, which she doesn't know about until the baby's leg is sticking out.
Teddy runs back to Pete's place and apologizes to him for flipping out on him. Pete and Darren forgive him.
Three months later, Teddy is helping Pete get ready to walk down the aisle. We learn that Teddy got a good job being a wedding planner, primarily for gay couples.
Mac and Kelly have now moved into their new home. They bring home their new baby, Mildred, to join Jimmy and Paula with their new son. Stella goes to play with her new sister.
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