NOTE: This spoiler was submitted by Jeremy.
In a suburban New York neighborhood, Special Agent Sarah Ashburn (Sandra Bullock) leads a team of officers into the home of a suspect. Right off the bat, we see how good she is as she deduces the suspect is hiding a big bag of marijuana under the coffee table by masking the smell with ribs to throw off the police dog's scent. Additionally, she uncovers a secret compartment of firearms in the wall. The other officers are annoyed by how proud of herself she is.
At night, Ashburn is watching TV at home with a large tabby cat. Turns out it's the neighbor's cat, and this isn't the first time she's done this. She checks her computer to learn that her superior Hale (Demián Bichir) is being promoted, and his former position is up for grabs. Ashburn goes into work the next morning hoping to secure the job based on her case records alone, but Hale tells her that none of the officers like her, a fact that surprises Ashburn. Hale decides to offer her a case in Boston to find a drug lord named Simon Larkin, and to locate his associate Julian Vincent (Michael McDonald) so he can lead her to Larkin. She accepts.
In Boston, Detective Shannon Mullins (Melissa McCarthy) is in her car keeping her eye on a man (Tony Hale) attempting to pick up a prostitute. Mullins busts him and even goes as far as calling the guy's wife, who tells Mullins to break his hand. She takes him into custody and passes by a neighborhood drug dealer named Terrell Rojas (Spoken Reasons). She catches him smoking a joint and chases him in her car, eventually running toward him and arresting him.
Ashburn drives to the Boston Police Department, taking Mullins' parking spot, to her dismay. She meets Captain Woods (Thomas F. Wilson) and goes to interrogate Rojas, despite Woods saying Mullins is going to take care of him. Ashburn tries to get Rojas to tell her where she can find Larkin, but Rojas fears he'll be killed if he spills the beans. She assures him he'll be fine if he gives her something, just as Mullins comes in and starts going at it with Ashburn, almost hitting her until Woods breaks it up.
The ladies are taken to Woods's office, where Mullins berates him in front of the whole department by saying he has "little tiny girl balls." She's pissed that he didn't have her back, and she storms out. Ashburn asks someone where she can find Mullins and is told that she'll be at a bar. Ashburn finds her at the bar to talk with her, and Mullins tries to grab her case files. She pushes another woman to create a diversion and swipes the case file when Ashburn isn't looking.
Mullins visits her brother Jason (Michael Rapaport) in prison. She asks him if he knows or was ever associated with Simon Larkin, but Jason denies it. He also says he is being released the next day.
Ashburn drives to the home of the supplier that Rojas told her about, only to find Mullins is already there. Due to Mullins's erratic behavior, Ashburn calls Hale and says she thinks Mullins is mentally ill, but Hale assures her that Mullins is the toughest cop, and her street smarts are essential. They reluctantly agree to start over and work together. On their walk to the apartment, a woman drives by and flips Mullins off. She reveals that is her mother.
Ashburn is ready to go in methodically, but Mullins says they are "the heat", meaning they take their perp down with force. Ashburn chooses to do it her way. They meet the supplier, Tatiana (Kaitlyn Olson), and they do the whole "good cop/bad cop" spiel. They get what they need and let Tatiana know the cops are coming.
The ladies stop in an apartment next to Tatiana's, which happens to be where Mullins lives. She shows off her stash of weapons, including a grenade and RPG, and she heads back with Ashburn to the station. They give Agent Levy (Marlon Wayans) what they have, and he briefs them on Larkin's distributor, Hank LeSoir (Adam Ray), who owns a club.
On their way out, the ladies are followed by a van, and they try to outrun it but are cornered. It's really two DEA agents, Craig (Dan Bakkedahl) and Adam (Taran Killam). Mullins mocks Craig for being an albino, but he hurls back a few misogynistic comments at the two women. Mullins walks away when she sees surveillance footage from the van and sees Jason hanging out with Julian.
Ashburn asks Mullins why she walked away from seeing the footage but manages to deduce that she saw her brother. She admits she read Mullins's file, and Mullins reveals that it was she who arrested Jason and locked him up after he got mixed up with bad company, which is why her family hates her. Ashburn tries to ease the tension but makes it worse.
The next day, Ashburn finds Mullins at her place reading her yearbook. She points out that only two teachers wrote in it, and she now considers herself even with Ashburn. She hugs her, and the two go to the Mullins household where the family is gathered to celebrate Jason's release from prison, but they are pissed to see Mullins there. While she goes to chat with Jason, Ashburn has to sit with the family, who asks her questions like if she's a narc, or if she used to be a man.
The ladies go to find Hank at his club. Mullins pulls Ashburn away since she is dressed too formally (as Mullins puts it, like she's gonna do their taxes). She rips the sleeves and legs off her clothes and pulls off her Spanx. Ashburn attracts Hank's attention, as well as a creepy clubgoer. The duo manages to switch the card in Hank's phone with another.
Ashburn and Mullins find Julian and Hank in a warehouse with other drug dealers. Hank almost assaults the women, but Mullins takes him down, kills one dealer, and takes Julian in. At the station, Craig berates the women for bringing both Julian and Hank in, and Hale is none too pleased either. The ladies once again try to get Julian to talk with their respective methods, with Mullins throwing a phone book in Julian's face and threatening to shoot him in the dick if he doesn't talk. To make it worse, Mullins only loads her gun with one bullet, forcing Julian to talk with each click on the gun, but he swears he doesn't know where Larkin is.
The ladies go to a bar, and Mullins gets Ashburn crazy drunk. From this, we learn a few things, like how Ashburn was a foster child, as well as her uncertainty in her capturing of a criminal known as the Red Falls Killer, which she constantly brags about. She wakes up hungover and learns that she gave her car keys to a guy named Wayne. He enters the car after refusing to give the keys back, only to be killed when it explodes.
Hale tells the duo that Julian escaped. To top it off, he sends Ashburn a picture of Mullins's family to threaten her. The ladies go picking up the Mullins family and the girlfriends of the brothers to bring them somewhere safe.
Mullins later gets a call from Jason, who tells her and Ashburn that a shipment of drugs is coming off a boat. The ladies lead a team of officers to where the ship is passing, but it turns out to be a party cruise, which is clean. Hale thinks the case is too much for Ashburn and doesn't think she ought to receive the promotion.
Ashburn and Mullins continue discussing the case over a meal at Denny's, when a customer begins choking on a piece of pancake. Ashburn tries to save him by making an incision in his throat, only making it worse as blood starts gushing everywhere. Mullins pounds his chest and the pancake pops out.
Ashburn is back at the station, talking to Levy after having been harsh earlier. He warms up to her, and there appears to be an attraction between them. She gets a call and learns that Mullins is at the hospital. She rushes there to find out from Mullins that Jason is in an induced coma after being shot. Ashburn pisses Mullins off again by saying the wrong things, and Mullins storms out, declaring Ashburn is not her partner.
Craig attempts to lead a team of officers with Adam to capture Larkin, mocking Mullins in the process. Ashburn sees this and curses out everybody in the room (except Hale), saying Mullins is a better officer than any of them.
Ashburn reconciles with Mullins, and they team up again, going after other drug dealers, which leads them back to Rojas. They dangle him over a fire escape until he tells them a drop is being made at a warehouse. They then accidentally drop Rojas on top of his car, but he's okay.
The ladies load up and head to the warehouse. They are cornered by Hank and other goons. He orders them to hand over their weapons in a bag. Ashburn and Mullins deliver one-liners and show off the pin pulled from the grenade, which blows up and sends the dealers off their feet. The duo makes a run for it but are captured and tied up by Julian. He sticks a knife in Ashburn's leg and leaves for a moment. Mullins grabs the knife and cuts herself free, but they hear footsteps, and she has to stick the knife back in Ashburn's leg. Craig and Adam come in, and the ladies think they are both working for Larkin. That's when Adam pulls out his gun and shoots Craig in the head, revealing that he is, in fact, Simon Larkin. He took on the drug business for a second source of income, and after learning from Mullins that Jason is alive, he goes off to finish him. Julian comes back to kill the ladies, but Mullins grabs the knife, cuts his face and knocks him out.
The duo makes it to the hospital. Mullins runs to Jason's room while Ashburn tries to roll herself in a wheelchair. Mullins finds Larkin trying to stick an air pocket in Jason's bloodstream. She tries to get him to stop, just as Ashburn is crawling to the room. Ashburn slides in, and when Larkin refuses to quit, she shoots him twice in the dick, to the surprise of Mullins.
Hale comes to congratulate the duo on their solving of the case. Ashburn tells him they should re-open the Red Falls Killer case. The duo almost leaves until they remember Ashburn's leg wound. Levy comes in and tells the doctors to give Ashburn the best treatment they can.
Mullins receives a promotion for her work at a ceremony that is attended by Ashburn and the whole Mullins family. Sometime later, the family visits Jason in the hospital, as he is now awake. Mullins calls Ashburn, who has decided to move to Boston and continue working alongside Mullins. Mullins tells her to look in her yearbook for a message that she wrote. The front page says "Fucking nerd", but the back page says "Foster kid - now you have a sister. Mullins." Ashburn smiles.
The credits begin, but then pause, as we see Mullins visit Ashburn, surprising her with the tabby cat from earlier, as Ashburn told her that it ran away. After some awkwardness, Mullins realizes the cat was never hers, and the two decide to bring it back to it's owner.
The credits continue.