In 1930s Mississippi during the Great Depression, three convicts—smooth-talking Ulysses Everett McGill, simple-minded Delmar O'Donnell, and hot-tempered Pete Hogwallop—escape from a chain gang with the goal of retrieving a buried treasure that Everett claims to have hidden before his incarceration. The trio sets out on an epic journey, journeying across the Southern wilderness to reach the money before the area is flooded for a hydroelectric project. Along the way, they encounter a series of colorful characters and obstacles, including a blind prophet who predicts their future, a one-eyed Bible salesman, and various other embodiments of Southern folklore and mythology.

Their adventure mirrors the classic Greek epic "The Odyssey" as they face trials that challenge their resilience and camaraderie. They are seduced by the enchanting song of the Sirens, outwit a cunning bible salesman, and encounter a political campaign that latches onto their unexpected fame. As they pursue their quest, they record a song that unexpectedly becomes a hit, unbeknownst to them. The law, represented by a relentless sheriff, is always close on their heels, and the convicts must use all their wit and resourcefulness to outmaneuver their pursuers. Their journey not only becomes one for hidden treasure but also transforms into a quest for self-discovery and redemption amidst the backdrop of the American South.