Ulysses Everett McGill, portrayed by George Clooney, is a charming and quick-talking convict who manages to escape from a chain gang in rural Mississippi during the tumultuous times of the Great Depression in 1937. He is shackled to two fellow prisoners: the dim-witted Delmar, played by Tim Blake Nelson, and the fiery Pete, depicted by John Turturro. Together, they embark on a quest driven by Everett's claim that he has hidden away a staggering $1.2 million after a botched armored car heist, and he promises to share the riches with his companions.
Their journey begins unexpectedly when they hitch a ride from a venerable blind man on a railway handcar, who cryptically predicts that they will find treasure, although "it may not be the one they seek." Stopping by Pete's cousin’s home, Washington Hogwallop, they receive a warm welcome until the authorities, led by the part-blind Sheriff Cooley (Daniel Von Bargen), arrive following a tip-off. The trio narrowly escapes as their temporary refuge goes up in flames, thanks to the courageous intervention of Hogwallop’s spirited young son, who drives them to safety in a car.
As they continue their adventurous trek, they stumble upon a religious baptism taking place in a river, with Pete and Delmar eagerly joining in the ceremony, much to the reluctance of Everett. Adding to their eclectic journey is a young black musician named Tommy Johnson, played by Chris Thomas King, who intriguingly mentions selling his soul to the devil for his unmatched musical abilities. This twist leads the group to a local radio station, where they perform "Man of Constant Sorrow" as the 'Soggy Bottom Boys,' earning them an unexpected sum of $40 while remaining anonymous.
But their newfound success comes with unforeseen consequences. Sheriff Cooley's relentless pursuit brings trouble to their camp, forcing them to split from Tommy. When they encounter notorious robber George 'Babyface' Nelson (Michael Badalucco), their trajectory shifts as they find themselves partaking in another heist. Following an enchanting, yet risky, encounter with three mesmerizing sirens by the river, Pete mysteriously disappears, leading Delmar to believe that the bewitching women have transformed him into a toad, discovered in Pete's discarded clothing.
Amidst further frivolity, they meet Big Dan Teague (John Goodman), a one-eyed Bible salesman who violently exploits their naivety, stealing their meager possessions. Down but not out, Everett and Delmar make their way to Everett's hometown to reconnect with his estranged wife, Penny (Holly Hunter), only to discover that she is engaged to another man, leaving him heartbroken.
Their efforts lead to an unexpected reunion with Pete, who admits he was forced to betray them after suffering under the relentless Sheriff Cooley's threats. Tensions rise when their path crosses with a hate-filled Ku Klux Klan rally, where they yet again disguise themselves to help their friend Tommy, ultimately leading to a chaotic confrontation that leaves Big Dan in peril.
In a surprising twist of fate during a political fundraiser, they perform once more, drawing cheers from the audience who recognizes the elusive Soggy Bottom Boys. However, their raucous celebration is interrupted by Homer Stokes, who tries to unveil their identities, but is swiftly 'ridden out on a rail' by the outraged townsfolk. This moment marks a significant turnaround for the group, as they receive an official pardon from the incumbent governor, Pappy O'Daniel.
As their journey nears its end, Penny's longing for the original wedding ring, which now rests at the bottom of a flooded valley, sets up a poignant reunion between her and Everett. Their adventure culminates dramatically as they barely escape an ambush by Sheriff Cooley’s men when the valley floods, allowing them to resurface and reclaim what they thought lost—both the ring and their sense of camaraderie.
With the compelling hymn "Angel Band" resonating in the air, Everett is left reflecting on the unpredictability and the twists of fate, standing by the side of his beloved Penny and their daughters as they cross paths again with the wise handcar operator who once predicted their journey.
