It's 1937 and Ulysses Everett McGill (GEORGE CLOONEY) is a silver-tongued, petty criminal who has convinced two other convicts, Delmar (TIM BLAKE NELSON) and Pete (JOHN TURTURRO), to escape from their Mississippi chain gang. After meeting a blind seer (LEE WEAVER) who tells them that they must travel a long and difficult journey before finding a fortune that won't be the one they're looking for, the three men set out for the treasure that McGill promised them and which reportedly will be at the bottom of a lake in four days.
As a solemn lawman, Sheriff Cooley (DANIEL VON BARGEN), pursues them, the three run into various interesting characters along the way. There's Tommy Johnson (CHRIS THOMAS KING), a young musician on his way to Jackson who claims to have sold his soul to the Devil in exchange for the gift of music. Then there's George "Baby Face" Nelson (MICHAEL BADALUCCO), a machine gun toting, manic depressive bank robber; a group of Sirens (MIA TATE, MUSETTA VANDER & CHRISTY TAYLOR) who seduce the men, and Big Dan Teague (JOHN GOODMAN), an unscrupulous, one-eyed Bible salesman.
Meanwhile, incumbent Governor Pappy O'Daniel (CHARLES DURNING) is in a heated campaign versus challenger Homer Stokes (WAYNE DUVALL), whose campaign manager, Vernon T. Waldrip (RAY McKINNON), is set to marry McGill's ex-wife, Penny (HOLLY HUNTER). With time running out and while dealing with all of those people and the various complications that come their way, the men discover that their quest has indeed changed into something else.