In 1932 Mississippi, we are introduced to Sammie Moore, who makes a painful entrance into his father's church, bearing a large claw mark on his face and clutching a broken guitar neck. His father, fearing the supernatural powers of music, implores him to abandon his musical aspirations and seek repentance for his choices.
Just the day before this troubling incident, Sammie's identical twin cousins, Smoke and Stack, both of whom are World War I veterans, return home to Mississippi after spending several years in Chicago. They share their disillusionment with the city, which they had expected to be a racial paradise. Armed with the funds they pilfered from local gangsters, the twins take a bold step by purchasing a sawmill from Hogwood, a notoriously racist landowner. Their dream is to establish a juke joint that will serve the black community of the area. To bring their vision to life, they recruit Sammie, a talented guitarist, as well as Delta Slim, who plays piano and harmonica, and a beautiful singer named Pearline. They also decide to include Annie, Smoke's estranged wife, along with Grace and Bo Chow, local Chinese shopkeepers, to handle catering for the much-anticipated opening night.
During this time, Stack awkwardly reconnects with his former girlfriend Mary, who appears white but secretly possesses one-eighth black heritage. Their encounter is marked by tension, as Mary feels abandoned by Stack, who expresses his belief that it would be impractical for a "white" woman to bond in matrimony with a black man. Meanwhile, Smoke finds himself at odds with Annie over her interests in the occult. She believes her rituals have kept them safe, despite the tragic loss of their infant daughter.
Enter Remmick, a desperate Irish immigrant hiding from pursuing Choctaws; he pays two Klansmen, Bert and Joan, for shelter but soon transforms them into vampires, revealing that the Choctaws were actually hunters of these monsters.
As the night of the juke joint opening arrives, the place fills with joyful patrons. The charming Stack and compassionate Annie persuade the skeptical Smoke to offer reduced prices to those who cannot afford the full fee. Sammie's captivating performance enchants everyone present, conjuring up spirits from both past and future without his own awareness. This spectacle catches the eyes of the trio, including Remmick, who rudely demands entry. Despite initial hesitations, Mary, eager for the cash, engages with them. In a shocking turn of events, Remmick transforms her into a vampire. Mary later seduces Stack, biting him in a deadly manner; although Smoke tries to shoot her, she remains unfazed and flees outside.
In the chaos that ensues, Annie convinces Smoke to evacuate the bar, inadvertently granting the vampires access to the unsuspecting patrons. As the situation spirals, Bo is also turned into a vampire, spelling disaster for the crew. The bar staff quickly learns that vampires cannot enter a building without an invitation, giving them a glimmer of hope. However, Stack arises as a vampire, prompting Annie to force him to retreat using pickled garlic juice. She advises the staff that only a silver weapon or wooden stake can eliminate their undead foes, handing Smoke a protective talisman.
Remmick attempts to negotiate with the remaining staff, asserting that unlike the Klan, he values Sammie's unique abilities and suggests that embracing vampirism bestows immortality, power, and freedom from racial hatred. Despite his tempting offer, the team resolutely declines. A distressed Grace spurs Remmick into action after he threatens her daughter, prompting a fierce conflict between the vampires and the remaining survivors.
The ensuing battle at the juke joint is harrowing. Amidst the chaos, Grace and Bo perish tragically in flames as she stakes him, while Annie is bitten by Stack and, out of love, requests her own mercy killing from Smoke. Delta Slim bravely sacrifices himself, fighting off a horde of vampires to allow others the chance to escape. The remaining survivors, consisting of Smoke, Sammie, and Pearline, make a desperate attempt to flee through the upper floor, only to be accosted by Remmick and the vampire Stack.
Smoke and Stack engage in a fierce duel, while Sammie and Pearline wrestle with Remmick. In a heartbreaking moment, Pearline tries to help Sammie but gets bitten in the struggle, urging him to make his escape. Sammie, ultimately managing to run to safety, encounters Remmick once more. In this final confrontation, Remmick attempts to seduce him to his side but is thwarted when Sammie shatters his guitar, inflicting a wound on the vampire. Just then, an arriving Smoke takes the opportunity to stake Remmick, leading to a shocking sunrise that obliterates the remaining vampires and signifies the end of the ordeal.
Following this climactic confrontation, Smoke sends Sammie home, revealing that his guitar was not a mystical instrument as Stack had suggested. As the day breaks, a group of Klansmen led by Hogwood arrives, intent on reclaiming the juke joint. Smoke valiantly confronts them, dispatching the assailants even as he succumbs to fatal injuries. In his dying moments, he is visited by Annie and their daughter in a vision, inviting him to cross into the afterlife.
The story loops back to Sammie, who is once again at the church with his father urging him to renounce his love for blues music. Defiant, Sammie grabs his guitar and heads north, embodying his love for music's potential.
In a mid-credits scene set in 1992, an older Sammie—now a celebrated blues musician—encounters a youthful and ageless Stack and Mary. A flashback reveals that Smoke made a deal with Stack, trading his life for Sammie's freedom. The couple offers Sammie a chance at immortality, which he rejects, despite Stack's request for him to play a song for nostalgia. In a poignant moment, Sammie admits that although he still has haunting nightmares from that night, it was nonetheless the best day of his life—a sentiment Stack deeply resonates with, as it marked his last moments with his brother and the sun, the only time he truly felt liberated.
