The film starts with a young African-American man named Cassius "Cash" Green (Lakeith Stanfield) at an interview for a telemarketing job at RegalView in San Francisco. The interviewer, Mr. Anderson (Robert Longstreet), points out that Cash lied about some details in his review, like his supposed bank job, as well as using his buddy Salvador (Jermaine Fowler) as a reference, when Sal already works for RegalView. However, Anderson sees that there is some potential in Cash as he is clearly ambitious, so he hires him and gives him a script that he will be using.
Cash lives in his uncle Sergio's (Terry Crews) garage with his girlfriend Detroit (Tessa Thompson) in nearby Oakland. Cash is broke and down on his luck. He frequently has thoughts of an existential crisis that he expresses to Detroit. Sergio also demands rent money from Cash that is four months late, because Sergio may soon have to sell his house.
Cash starts working at RegalView with the calls, finding himself appearing as though he is there in the home of the people he is calling, but his lack of confidence in his presentation leads the people to hang up on him. The older caller sitting next to him, Langston (Danny Glover), tells Cash that he can get more clients by using a "white voice" instead of his African-American style of speaking. Langston demonstrates with the use of his own white voice (voice of Steve Buscemi).
During a work meeting, Cash asks when the team will get raises, which is laughed off by Diana DeBauchery (Kate Berlant), the lady holding the meeting. Afterward, Cash meets a co-worker named Squeeze (Steven Yeun), who took notice of Cash's question. He invites Cash out for drinks later, along with Sal and Detroit.
At the bar, there is an ad for a company called WorryFree, which offers secure jobs, housing, and food, but a protest group called Left Eye believes that WorryFree's employees are being for slave labor to cut back costs, so they frequently vandalize their billboards across the city. Cash and his friends gather for their drinks, and Cash makes a toast in his white voice (voice of David Cross), which stuns the others.
Cash starts to utilize the white voice at work, which earns him lots and lots of sales. However, Squeeze leads all the callers to protest against RegalView since WorryFree is their biggest client, as well as more raises in their payment. They lead a chant of "F*** you, RegalView!", leading the bosses to call Cash into their office. He starts to tell them off, but they tell Cash that his work has proven to be so exceptional that he is being given a raise and moving on up to the top floor reserved for Power Callers.
As a Power Caller, Cash starts to make a lot more money. He is able to pay back Sergio in full, and he moves himself and Detroit into a swanky new apartment along with purchases of a better bed, TV set, and many expensive decorations. Because he is making so much more money, Cash ends up abandoning the workers union, crossing their picket line to go to work while claiming he will support them from the sidelines. This causes a rift between him, Sal, and Squeeze, and Detroit tells him that they are done if he continues to work for RegalView. On his way past the protest line, a Left Eye protester named Cynthia Rose (Indigo Jackson) tosses a soda can at his head, making her a viral sensation while Cash becomes a laughingstock.
Cash meets another Power Caller known as Mr. ____ (Omari Hardwick) (his name gets bleeped whenever someone says it), who always speaks in his white voice (voice of Patton Oswalt). He tells Cash that he can get him to meet with Steve Lift (Armie Hammer), the CEO of WorryFree.
Cash attends a performance art show held by Detroit. Using her own white voice with a British accent (voice of Lily James), she tells the patrons that there are bowls filled with phones, bullet casings, and balloons filled with sheep blood that they can pelt her with as she recites lines from the film "The Last Dragon". The people do so, and Cash is horrified to the point that he interrupts the show. Detroit tells him it's part of the show, and he leaves.
Cash goes to a party at Steve's place with Mr. ____. Everyone gets high on cocaine and an orgy takes place. Steve asks Cash to sing a rap, but he's bad at it so he only sings "N**** shit! N***** shit! N**** n**** n**** shit!" with everyone repeating it like it's a hot lyric. Steve asks Cash to meet with him in private. Before doing so, Mr. ____ has a heart-to-heart with Cash as he drops his white voice for the first time.
Steve offers Cash a line of coke before Cash asks to go to the bathroom. He goes into the wrong room and finds someone asking for help in a stall. Cash opens the door, and out falls a half-human/half-horse monstrosity, along with other creatures just like him. Cash freaks out as Steve finds him. Steve explains that they are "Equestrisapiens", and he shows Cash a video demonstrating WorryFree's belief that humans can be used as tools for their own personal gain, and that the coke is the serum that causes the transformation, although Steve is adamant that he gave Cash regular coke. He offers Cash the chance to join, with the promise of $100,000,000 and only having to be like that for five years before being given an antidote. Cash firmly refuses and he walks out.
After the performance show, Detroit is seen hooking up with Squeeze.
Cash wakes up panicked, thinking he is still high. He talks to Detroit after thinking he has started to mutate. Detroit shows him a video from his phone that got lost, which shows the Equestrisapiens begging for help before Steve comes in and threatens to turn them to glue. Cash plans to expose WorryFree with the video by going on a popular show called "I Got The Shit Kicked Out of Me". Cash must subject himself to humiliation by getting beaten up on live TV before being dunked in a tank of actual shit, before they play the video on his phone.
The video only brings in good publicity for WorryFree, sending their stocks soaring and making other crazy people see Steve as some sort of messiah. Cash only becomes even more of a laughingstock.
Cash reconciles with Sal and Squeeze after enduring all of his recent trauma. He gets back with Detroit as well, who admits that she fooled around with someone else, but it doesn't bother Cash.
Cash joins his friends and the rest of the RegalView callers as they are joined by a large number of protesters outside of RegalView's building. A police SWAT team tries to break them up, only for the protesters to hold them back using statues from Detroit's show, as well as football players from Cash's high school. As the riot grows more chaotic, Cash and his friends hide, until one of the officers knocks Cash out.
Cash wakes up in a police van as he watches the madness continue to unfold. Another van attempts to run over a group of protesters, but they are held back by the escaped Equestrisapiens, who manage to overpower the police with their superhuman strength. The lead Equestrisapien, Demarius (Forest Whitaker), frees Cash and his friends before he and his mates retreat into the night.
Cash moves back into Sergio's garage, but he redecorates it to look nicer. He gives the nicer car that he bought as an apology gift to Sal. Detroit moves back in with Cash. Just before they get comfortable, Cash feels something painful on his nose. Detroit takes a look and sees that Cash's nostrils look horse-like.
Before the credits roll, Steve is in his house until he sees Cash (now fully transformed into an Equestrisapien) leading the other Equestrisapiens to storm into his house. Cash breaks down the door and lets out a frightening roar.