Ulysses Everett McGill (George Clooney), a suave, fast-taking convict, escapes from incarceration in Mississippi during the Great Depression. He is chained to two other prisoners, slow-witted Delmar (Tim Blake Neslon) and hot-tempered Pete (John Turturro), so the three must escape together. Everett convinces them that he has hidden $1.2 million after robbing an armored car, and promises to split it with them. They hitch a ride with an elderly blind man on a railway handcar, and he foretells that they will indeed find a treasure, though it may not be the one they seek.

They travel on foot to visit Pete's cousin, Washington Hogwallop, who removes their shackles and allows them to sleep in his barn. However, the trio is awakened by the
However, Everett reveals that he fabricated the story to entice Pete and Delmar to escape with him. Everett had truthfully been arrested for practicing law without a license, and was determined to escape when he heard his wife planned to remarry. If caught, the trio could face an additional 50 years in jail. An enraged Pete tackles Everett.

The three stumble upon a Ku Klux Klan rally in a nearby field. Shocked, they see that Tommy Johnson had been captured and that the Klan is preparing to hang him. The trio disguise themselves as color guard members and attempt to rescue Tommy, but are confronted by Big Dan Teague, a member in attendance. The Grand Wizard, it so happens, is candidate for governor Homer Stokes. After a scuffle, Everett, Pete, and Delmar topple a huge fiery crucifix onto Big Dan, presumably killing him, and escape with Tommy.

The four men arrive at a campaign dinner, disguised by long false beards. Pretending to be the hired band, they slip onstage and entertain (Delmar sings an impressive version of "In the Jailhouse Now") while Everett attempts to speak to Penny again. When the men launch into "Man of Constant Sorrow", they watch in awe as the entire audience rises to its feet and cheers, recognizing them as the elusive Soggy Bottom Boys. However, Homer Stokes arrives and tries to reveal them as the men who disrupted the lynch mob in performance of its duties. The townspeople are outraged at Homers confessed racism, and