On October 15, 1932, twin World War I veterans Smoke and Stack Moore return to Clarksdale, Mississippi, using stolen mob money to open a juke joint for the Black community. Joined by their cousin Sammie, pianist Delta Slim, singer Pearline, and Smoke’s estranged wife Annie, they create a space for joy and music—despite opposition from local racists and Sammie’s pastor father, Jedidiah.

Meanwhile, Irish vampire Remmick arrives in Mississippi, turning Klansmen into his undead followers. When Sammie's music unknowingly summons spirits, Remmick targets the juke joint. The twins refuse his offer of money and partnership, but he retaliates: Stack is turned by Mary, his ex-lover now a vampire, and patrons are slaughtered. Annie, armed with spiritual knowledge, helps defend the survivors but is killed after Grace, a desperate ally, unknowingly invites the vampires inside.

Smoke fights his now-vampiric brother as Sammie and Pearline confront Remmick. Smoke ultimately saves them as dawn burns the vampires. He then ambushes and kills Hogwood and the Klan but is fatally wounded. Dying, he sees a vision of Annie and their daughter.

Sammie, traumatized but alive, rejects his father’s call to abandon music. Sixty years later, an ageless Stack and Mary visit the elderly Sammie, now a blues legend. They offer him immortality; he declines. After playing one last song, Sammie reflects that despite the horrors, that night was the freest he ever felt—and the last time Stack saw the sun.