Three convicts, Ulysses Everett McGill (George Clooney), Pete Hogwallop (John Turturro) and Delmar O'Donnel (Tim Blake Nelson) escape from a chain gang and set out to retrieve a supposed treasure Everett buried. The three get a lift from a blind man driving a handcar on a railway. He tells them, among other prophecies, that they will find a fortune but not the one they seek. The trio make their way to the house of Wash, Pete's cousin. They sleep in the barn, but Wash reports them to Sheriff Cooley, who, along with his men, torches the barn. Wash's son helps them escape.
They pick up Tommy Johnson, a young black man. Tommy claims he sold his soul to the devil in exchange for the ability to play guitar. In need of money, the four stop at a radio broadcast tower where they record a song as The Soggy Bottom Boys. That night, the trio part ways with Tommy after their car is discovered by the police. Unbeknownst to them, the recording becomes a major hit.