In Depression-era Oklahoma, Tom Joad hitchhikes home after being paroled from the state penitentiary. Along the road, he encounters Jim Casy, a preacher Tom remembers from childhood. Casy explains that he is no longer a preacher, having lost his calling. He still believes in the Holy Spirit, but not necessarily the spirituality mandated by organized religion. For Casy, the Holy Spirit is love. Not just the love of God or Jesus, but the love of all humans. He maintains that all people are holy, everyone being part of the whole soul of humankind. Tom invites Casy to join him on his walk home.
When they arrive at what was once the Joad farm, Tom and Casy find it abandoned. Muley Graves, a Joad neighbor, approaches and tells Tom that his family has been tractored off their land by the bank. They have moved in with his Uncle John and are preparing to leave for California to find work. Tom and Casy spend the night near the deserted farm and head to Uncle John's early the next morning.
The family is preparing for their journey to California when Tom and Casy arrive. Casy asks whether he can journey west with the Joads. The Joads agree to take him along. Once their belongings have been sold, everyone except Granpa is anxious to get started. They pack the truck, but Granpa has decided he wants to stay on the land, and they must drug Granpa in order to get him in the truck. They are on the highway by dawn.
The family stops that first evening next to a migrant couple whose car has broken down. The Wilsons are gracious, offering their tent to Granpa who has a stroke and dies. Tom and Al fix the Wilson's car, and the two families decide to travel together.
In New Mexico, the Wilson's touring car breaks down again, and the families are forced to stop. Granma has become increasingly ill since Granpa's death, and Tom suggests the others take the truck and continue on. Ma refuses to go, insisting that the family stay together. She picks up the jack handle to support her point, and the rest of the family gives in. As they reach the desert bordering California, Sairy Wilson becomes so ill that she is unable to continue. The Joads leave the Wilsons and continue across the California desert on their own.
Granma's health continues to deteriorate, and as the truck starts its nighttime trek across the desert, Ma knows that Granma will not survive. Knowing that they cannot afford to stop, Ma lies in the back of the truck with Granma. Midway across the desert, Granma dies. By dawn, the Joads have climbed out of the desert and stop the truck to gaze down upon the beautiful Bakersfield valley. Ma tells them that Granma has passed. She must be buried a pauper because the family does not have enough money to bury her.
The Joads stop at the first camp they come to, a dirty Hooverville of tents and makeshift shelters. The men are talking to Floyd Knowles, a young man in the camp, when a businessman accompanied by a cop offers them work. When Floyd asks for a wage offer in writing, he is accused of being a "red," and the cop attempts to arrest him. Tom trips the cop, and Casy kicks him. When the cop regains consciousness, Casy gives himself up to the law in order to divert attention away from Tom. The Joads immediately leave to avoid any further trouble.
The Joads travel south to a government-run camp in Weedpatch. Here, the community governs itself, electing committees to deal with clean-up, discipline, and entertainment. The Joads are comfortable but, after a month, are still unable to find any work and realize they must move on.
They are offered work picking peaches in Tulare. The camp gate is surrounded by a large group of men shouting and waving. The Joads, escorted through the gate by state police, begin work immediately. They are paid five cents a box, not sufficient to feed the family a day's meal. After the first day of picking, Tom wanders outside the ranch. He meets up with Jim Casy, who is leading a strike against the peach orchard owners who want to pay two-and-a-half cents a box. Tom learns his family is being paid five cents because they are working as strikebreakers. As the men talk, authorities sneak up, looking for Casy, the presumed leader of the strike. Unprovoked, one of the men strikes Casy on the head, killing him. Without thinking, Tom begins beating Casy's killer. The other men intervene, and Tom's nose is broken. He escapes, hiding in the peach orchard until he can reach his house.
Marked by his scarred face and broken nose, Tom becomes a fugitive, hidden by his family. The Joads flee the peach ranch at the first daylight. They find work picking cotton and share an empty boxcar with another family, the Wainwrights. Tom hides in a nearby cave where his mother leaves him food. The family is comfortable for a time, earning enough to eat meat daily. One day, however, young Ruthie gets in a fight with another child. She threatens to call her big brother who is hiding because he has killed two men. Ma rushes to tell Tom he must leave for his own safety. Tom agrees and leaves with plans to carry on the social work that Jim Casy has begun.
Al gets engaged to sixteen-year-old Agnes Wainwright. As the cotton picking slows, the rains come. It rains steadily, and the water levels begin to rise. The night that Rose of Sharon goes into labor, the river threatens to flood the boxcar. Pa, Uncle John, Al and the rest of the men try to build an embankment to contain the river, but are unsuccessful. Rose of Sharon's baby is stillborn.
After a few days, the rain subsides. Leaving Al and the Wainwrights, the remaining Joads abandon the boxcar for higher ground. They find shelter in an old barn already occupied by a boy and his starving father. The child tells the Joads that his father has not eaten in six days and is unable to keep down solid food. Rose of Sharon offers him the breast milk no longer needed for her own child. The others leave the barn as she cradles the dying man to her breast.