O Brother, Where Art Thou? opens with Everett, Pete and Delmar escaping from prison by running away from the chain gang they are working on and making their way to Pete’s cousin’s home. On the way there they meet a blind man pumping a handcar on the railroad tracks. They hitch a ride and he prophesies that they will not find the treasure they are after, but will be rewarded in unexpected ways. Soon after they make their way to the house of Wash, Pete’s cousin. He helps them remove their shackles, but while they are sleeping, cops surround the barn they are sleeping in; Pete’s cousin has given them up for the reward money. The police set the barn on fire, but the boys are able to escape after the son of Pete’s cousin drives into the barn and drives them away to safety.
After they've escaped, the boys ditch the kid and take the car. They find themselves in a forest just as a group of churchgoers are walking to the river to get baptized. Delmar and Pete take the opportunity to get baptized themselves. Later on the road, they pick up Tommy Johnson, a black guitar player who’s just sold his soul to the devil in exchange for being able to play his guitar. Tommy is on his way to have a song recorded by a man that pays good money for recordings. The boys decide to go with him to the recording studio. They call themselves “The Soggy Bottom Boys” and record their first song and get paid. That night when the cops find their car, Tommy runs off and the boys escape the law to run another day. Everett has told Pete and Delmar that there is a treasure he’s stolen ($1.2 million) hidden away and that if they help him get to it he will split it with them. While walking on the road the next day they are picked up by George “Baby Face” Nelson who robs a bank with the boys, gives them their cut and then leaves. Next on their journey, the boys are enchanted by three women singing while washing clothes in the river. The women are modern Sirens, who lure travelers away from their journeys. They boys fall for the women and end up passing out on the river banks. When they wake up, Pete is gone. Everett believes he’s dead and Delmar believes he’s been turned into a toad left behind, so they take the toad with them on the next leg of their journey. At a restaurant, they meet Big Dan Teague, who tells Everett and Delmar that he has an opportunity for them making money selling Bibles. After convincing the duo to buy him lunch, he takes them to a secluded field where he beats them and takes their money. To top it off he kills the toad.
Meanwhile, Pete is neither dead nor a toad. Rather, he's been apprehended by the authorities and is being whipped for information on Everett and Delmar's location. The next day Everett thinks he sees Pete working on a chain gang, but assumes it’s the heat getting to him. Everett and Delmar ride the truck into town and Everett sees three little girls singing on a stage. He goes to them and we find out they are his daughters, and their mama, Penny, is engaged to another man. Everett goes to confront Penny and ends up taking a beating from her fiancé. Down on their luck, Delmar and Everett go to see a picture show where a chain gang is led in to watch too. Pete is among the prisoners and he whispers to Everett and Delmar not to go after the treasure. That night Everett and Delmar break Pete out of jail, but Everett has a confession: there never was any treasure. He only wanted to get free to stop his wife’s wedding. This realization enrages Pete because he only had two weeks left on his sentence and now he will be in prison until he’s in his eighties. Pete hits Everett and the two men begin to fight, but stumble upon a Ku Klux Klan meeting in the middle of a field. The Klan is planning to lynch Tommy. The boys can’t let that happen and they rescue their friend from certain death.
With Tommy now in their group, the Soggy Bottom Boys go back into town and disguise themselves to perform at a campaign dinner for gubernatorial candidate Homer Stokes, who also happens to be the head of the Ku Klux Klan. While they were on the run, the Soggy Bottom Boys' recording that they did in the studio has become massively popular and the attendees at the dinner cheer wildly for the musical act. When Homer Stokes attempts to stop the Soggy Bottom Boys from performing, he is carried off and booed. Seizing his opportunity to sway voters, the competing candidate Pappy O'Daniel expresses allegiance with the Soggy Bottom Boys, pardons them of all their crimes, and nominates them to be on his special council.
Everett convinces Penny to marry him again, but only if he goes to their cabin and retrieves her old wedding ring. He doesn’t want to, but does, and the boys join him. When they arrive there is a lawman there waiting for them with nooses hanging from the tree; he plans to hang the boys. The boys are tied up and told to say their prayers. For the first time Everett begins to pray for forgiveness and help. Within seconds we see water trickling onto the soil. A tsunami of water floods the area and the boys are swept away and saved from execution. He finds his old desk floating in the water and brings Penny back her ring. When he gets back, however, she points out that he got the wrong ring and demands he find the right one at the bottom of the lake. The credits roll.
