The film starts with lifelong best friends Mia Carter (Tiffany Haddish) and Mel Paige (Rose Byrne) talking on the phone about Mia having a sex dream about Barack Obama. They then walk into the bathroom from their own separate rooms, proceeding to get ready for the day.

The ladies have known each other since childhood and have opened their own make-up company, Mia & Mel, which they run with their employees/friends Barrett (Billy Porter) and Sydney (Jennifer Coolidge). As they arrive to work, Mia takes over for Sydney to put make-up on a teenage girl who is going to homecoming. Meanwhile, Mel looks over their expenses and sees that they are in serious debt and are overdue on payments since Mia is irresponsible with money. This is shown as she gives the girl a “cute nerd” discount.

Mia and Mel then go to the baby shower for their friend Kim (Jessica St. Clair), joined by other close friends Jill (Natasha Rothwell) and Angela (Ari Graynor). The other ladies, including Kim’s aunt, make patronizing comments regarding the ladies’ make-up business. They escape the annoyance by going upstairs to smoke a joint, not realizing Jill’s baby son Rider is in his crib. They try to leave but hear the others coming upstairs, so they try to sneak out the window, but Kim, Jill, and Andrea spot them. After expressing their frustration with their criticisms, Mia and Mel jump into the pool to get away.

The next day, the ladies go to work to find a young man, Josh (Karan Soni), arriving on behalf of his boss Claire Luna (Salma Hayek), who wants to buy Mia and Mel’s business to incorporate into her own company, Oviedo. Mel immediately accepts the invite, but Mia is skeptical because she doesn’t want to have to answer to anyone. They go to Oviedo to meet Claire, and while Mel is still fully on board to join, but Mia finds Claire too suspicious. After Mel spells out to Mia just how much debt they are in, they decide to take the night to consider things.

Mel takes Mia to a drag bar where they drink and go up to sing karaoke. Although Mia knows what Mel is trying to do, she is moved and convinced to go along with the deal. They return to Oviedo the next day to sign the papers, wherein they would own 51% of their company and have their debts wiped clean. Claire instructs them to come up with a new product to bring her by the next day.

That night, the ladies go to a party for a younger guy that Mia is hooking up with. While lacking inspiration from the pairs of friends they encounter, they smoke a joint and talk about how much they have always looked out for each other, so they decide to record the other best friends at the party.

Mia and Mel bring a video that they edited overnight with all the friends, using it as a jumping point for their new product, “Proud”. However, Claire is unimpressed and takes more interest in an older make-up kit product that the two made. They take a visit to their shop where Claire meets Barrett and Sydney. After she notes that Barrett (who is in charge of crafting the products) isn’t working fast enough, she orders Mel and Mia to fire him. Reluctantly, the two take Barrett out to dinner and clumsily attempt to fire him before they are forced to spit it out. He then makes an overly dramatic exit.

Tensions rise among the ladies after the firing, as well as what seems like Mel sucking up to Claire. They have dinner that night with Kim, Jill, and Andrea where they have a chef show them how to make their own ceviche and chilis rellenos. Mia and Mel passive-aggressively argue, leading to Mel sneaking extra ghost peppers in Mia’s chili. This causes Mia to suffer painful burns in her mouth, and when Jill tries to calm her down with goat’s milk, Mia spits it up in her face. This leads Jill to angrily throw Mia and Mel out.

Mel apologizes to Mia over what she did, especially since they need to bring Claire a product for her to present for an upcoming beauty convention. They fail to come up with something good, so Claire plans to give their spot to two misogynist make-up creators, Ron (Jimmy O. Yang) and Greg (Ryan Hansen), who run GET SOME for what they believe to be women who secretly only wear make-up just to impress men. Claire gets pissed to the point of forcing Josh to stay behind while she rides back to work without him. He then informs Mia and Mel that if anything were to happen for their partnership to dissolve, they would only own 49% of the company and have to give Claire 49 cents for every dollar they make for the rest of their lives.

The ladies head over to Oviedo to demand that Claire give them another shot. Even as security tries to get them out, Mia threatens to jump over a ledge if Claire doesn’t see them. This leads to her actually almost falling until she catches onto a flag and is pulled back by everyone. This gets Claire to see them, but it also serves to highlight Claire’s thoughts that best friends can’t work together since she parted ways with her former best friend before running her company. Claire decides to let them test their skills at a make-up presentation later that night.

Mia and Mel attend the presentation to compete against Ron and Greg to do make-up for twin sisters. The ladies try their teamwork approach to give the first girl a simple touch-up, while the guys doll up the other girl to “cover up her flaws”. After the guys receive a more positive reception from the audience, Claire starts to get Mia and Mel to turn against each other by getting them to argue about what they can’t stand from each other (Mel being a pushover and Mia being difficult to deal with), leading Mia to quit. Mel chases after her, but they part ways right there.

Over the next few weeks, Mia and Mel don’t talk to each other. Mia takes the time to reconcile with Barrett, while both ladies get reassurance from their three friends over their business. Mel then finds out from Sydney that Claire is going with Ron and Greg at GET SOME for the make-up convention, and they are using a rip-off of their earlier make-up kit. Mia then calls Mel as she tries to say sorry, but they end up running into each other on the streets where they hug and forgive each other. Mel informs Mia over what Claire is trying to do, and they round up their friends to help them pull something off.

Everyone goes to the make-up convention where Claire is about to introduce Ron and Greg, but Mia and Mel hijack the presentation and use the others to stop Claire from doing anything. Mia and Mel present a new make-up kit that emphasizes the importance of how it is the work of best friends. The crowd is impressed and loves what they have done. Claire confronts them and reminds them that they are still signed under her. After delivering a nasty insult to Claire’s face, Mia and Mel bring out Shay Whitmore (Lisa Kudrow), Claire’s former best friend that she cut ties with. The two now work under Shay, and since they still own 49% of their company under Claire, it will be Claire who is forced to pay them $49 million. Mia and Mel celebrate their victory with karaoke.

One year later, Mia and Mel’s new business, Proud Beauty, has become hugely successful to the point where they are planning to expand internationally. They give the good news to Barrett and Sydney, who now work under them. Mia and Mel celebrate the fact that they have officially made it.

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Best friends Mia and Mel run their own make-up business, but they are falling into serious debt. Claire Luna, CEO of cosmetics company Oviedo, wants to buy their business. Although the two sign-on, it quickly becomes clear that Claire is trying to drive a wedge between the two of them.

After briefly splitting Mia and Mel up, Claire plans to launch a new product with a different make-up duo (two misogynist guys) that rips off one of Mia and Mel's earlier products. The two show up to the convention where the launch is taking place and use their friends to hijack the show and present their own original product that highlights the importance of best friends. The crowd loves it, and Mia and Mel tell Claire they are working with her own former best friend Shay Whitmore. Furthermore, Claire will be forced to keep paying Mia and Mel due to them now owning 49% of their brand under her.

One year later, Mia and Mel's new business is thriving and ready to expand internationally.