In late 1930s Chicago, Sister Rosetta Tharpe begins working as an exterminator for Stump Prevention Control (SPC), a newly established government agency. SPC is tasked with eradicating “stumps”—dangerous growths of spores which, if allowed to mature, explode and kill everyone in their vicinity. Stumps grow where people have recently died; they take on the deceased’s likeness and resemble wooden statues. Because the spores that make up stumps are highly infectious, folks don face masks and use heavy-duty air filters.

The SPC has discovered that a small number of singers possess a unique vocal resonance which causes the stumps to mature and burst safely. However, if the singer continues for too long, they might trigger an explosion, so each singer is paired with a handler, who instructs them when to stop singing and deals with the technical work of vacuuming the stump dust. Rosetta’s handler is Marty Houchen, an easygoing white man.

Besides Rosetta, the only other Black female exterminator in Chicago is Lizzie Douglas, who goes by the stage name Memphis Minnie. Unlike the acquiescent and religiously devout Rosetta, Minnie is brash, doesn’t enjoy being told what to do, and has already gone through several handlers. When Rosetta introduces herself to Minnie, Minnie is rude and dismissive.

Three weeks later, Rosetta notices Minnie sneaking up to the roof of the SPC building. She follows her and finds her singing out in the open. Because Minnie has no handler to check her, she risks causing an explosion if there are any stumps nearby. Worried, Rosetta warns Minnie, but she also chooses not to report her to their superiors. Minnie apologizes for their first meeting and invites Rosetta to the Alley Cat, an underground nightclub where people sing for pleasure. That night, Rosetta visits the Alley Cat, which is intensely guarded to evade the gaze of the SPC. Minnie comes on stage to sing, and Rosetta watches in awe as she performs.

Rosetta begins frequenting the Alley Cat; Minnie is able to draw Rosetta out of her shell, and the two grow closer. One day, Minnie sees Marty in the club and panics, but then realizes that he and Andre, the owner of the Alley Cat, are romantically involved. Marty agrees not to tell the SPC about the club if Minnie doesn’t tell Rosetta about him and Andre. However, the Alley Cat is shut down when Minnie’s new handler follows her and Rosetta there. The SPC storms the club and finds stump dust in a small closet.

After the Alley Cat is forced to close, Minnie stops going to work. Rosetta and Marty find her at home, drunk and lying face down on her kitchen floor. After helping her sober up, Rosetta confronts Minnie, saying that the club was dangerous and her singing could’ve caused the stump dust to explode. Rosetta reveals that she had wanted to move to New York to pursue her dreams as a singer, but her husband, Thomas, wasn’t entirely on board. While her mom and Thomas went to New York, Rosetta stayed behind in Chicago to begin the process of divorcing him. In New York, Rosetta’s mom and Thomas died in a stump explosion; Rosetta blames herself and her ambitions for their deaths. She hasn’t sung, outside of extermination, since her mom’s death. She says the stumps are God’s punishment and calls Minnie a sinner for singing in the Alley Cat. Minnie tells Rosetta to leave and breaks dishes in anger.

Later, Minnie rides the bus and, lost in her thoughts, misses her stop. She has to get off at Bridgeport, a white neighborhood. Because Chicago is segregated, Minnie receives unfriendly stares as she walks through Bridgeport. She comes across an alley with a row of uncovered stumps. Suddenly, she comes face to face with a gang of white men, who threaten her to get out of their neighborhood. Minnie explains that she is from the SPC—but the men distrust the SPC: the exterminator responsible for their area has mysteriously disappeared, and stumps have begun appearing all over Bridgeport out of nowhere. They believe the SPC has planted them and that they want the whole city of Chicago to go into quarantine.

The men rush toward Minnie, but she starts singing in self-defense. She continues long past the normal duration to pulverize the stumps, and all of them—she and the white men—experience the memories of the deceased people whom the stumps resemble. Minnie realizes that SPC lied about the dangers of singing too long (allegedly, it would cause convulsions, bulging eyes, and bloody sputum). For some reason, the agency tried to cover up this “residual memory.”

The SPC takes Minnie into custody. Rosetta learns about the cover-up from one of the Bridgeport men. Marty reveals that he knew all along, but was too scared to talk after Bridgeport’s exterminator discovered the SPC’s secrets and was detained. Rosetta feels betrayed.

Rosetta and Marty come to rescue Minnie at the SPC. Outside the building, crowds of people protest, but the SPC officials shoot at them, turning civilians into stumps. Rosetta realizes that the SPC wanted the city to go into quarantine in order to test using the stumps as weapons.

Rosetta stands on top of her and Marty’s car. She plays guitar and sings—for real—for the first time since her mom’s death. All the memories of the surrounding stumps flood into her. She realizes that she’s supposed to sing them down—the stumps want their memories to live on. She breaks into the SPC and saves Minnie.

The FBI investigates the SPC and finds that it planted stump spores in poor neighborhoods, kidnapped people, and experimented on the homeless. Rosetta and Minnie agree to establish a new stump removal agency on the condition that Andre gets the Alley Cat back.

At the Alley Cat, Rosetta performs and invites a new exterminator, Marie Knight, on stage with her. The two play a song and have obvious chemistry. In the audience, Marty asks Minnie whether Rosetta will ever trust him again. Minnie, noticing Rosetta and Marie, tells Marty to let Rosetta know about him and Andre: “I got a feelin’ she won’t mind.”