Loosely based on Homer's 'Odyssey' the movie deals with the picaresque adventures of Everett Ulysses McGill and his companions Delmar and Pete in 1930s Mississipi. Sprung from a chain gang and trying to reach Everetts home to recover the buried loot of a bank heist they are confronted by a series of strange characters. Among them sirens, a cyclops, bank robber George 'Babyface' Nelson (very annoyed by that nickname), a campaigning Governor, his opponent, a KKK lynch mob, and a blind prophet, who warns the trio that "the treasure you seek shall not be the treasure you find."
In 1937, Ulysses Everett McGill (Clooney), Pete Hogwallop (Turturro), and Delmar O'Donnell (Nelson) escape from a chain gang at Parchman Farm and set out to retrieve the $1.2 million in treasure that Everett claims to have stolen from an armored car and buried before his incarceration. They have only four days to find it before the valley in which it is hidden will be flooded to create Arkabutla Lake as part of a new hydroelectric project. Early in their escape, while still chained together, they try to jump onto a moving train with some hobos, but fall off due to Pete's inability to get on. They then encounter a blind man (Weaver) traveling on a manual railroad car. They hitch a ride, and he foretells their futures. They "seek a great fortune" and they will "find a fortune, though it will not be the one they seek". They will also see many wonders on their journey, including a "cow on the roof of a cotton house".
They walk to Pete's cousin's house, Wash Hogwallop (Frank Collison), who removes their chains, but, because he needs the money, he then turns them in to the police, led by Sheriff Cooley (von Bargen). The authorities set the barn they are sleeping in ablaze, but the trio quickly escapes with the help of Wash's son. When they pass a congregation on the banks of a river, Pete and Delmar are enticed by the idea of baptism, to the immense derision of the skeptical Everett. As the journey continues, they travel briefly with a young guitarist named Tommy Johnson (King). When asked why he was at a crossroad in the middle of nowhere, he reveals that he sold his soul to the devil in exchange for the ability to play the guitar. Tommy describes the devil as being "White, as white as you folks ... with empty eyes and a big hollow voice. He love to travel around with a mean old hound". This description matches Sheriff Cooley.