Tom Joad returns home from serving four years in prison for killing a man. The home he returns to is deserted, because his family, who are tenant farmers, have been thrown off their land by the bank which owns the farm. The Dust Bowl has caused the topsoil to blow away and little can be grown in the fields. Along his journey home Tom meets up with former preacher Jim Casy. He and Jim find the Joad family at Tom's Uncle John's home as they are about to start their journey to California. They have been told the jobs are plentiful there and the wages are high. Tom decides to accompany his family to California, even though it would be a violation of his parole to leave Oklahoma.

Tom's five siblings, including his sister Rosasharn, who is pregnant and her husband Connie, Uncle John, Grampa and Granma, Pa and Ma, and Jim Casy all pile into the truck for the trip. After traveling awhile, they decide to camp along the road for the night. They camp beside Ivy and Sairy Wilson, who are also on their way to California. While alongside the road Grampa has a stroke and dies. They bury him beside the road. The two families decide to pool their resources and travel together.

The next day the car's con-rod bearing breaks causing the little convoy to halt. Tom wants the family to continue on toward California, while he and Casy stay behind and fix the car. Ma says she will not allow the family to be broken up. So instead the rest continue on to find a place to camp and Al comes back with the truck to pick up Tom. The car is fixed that evening and the men catch up with the family at the camp. Granma is sick by the time they return to the camp. A man in the camp tells the others there is little work in California, in fact his wife and children died of starvation.

The Joads make it into California and find a camp in which to stay. The Wilsons are still traveling with them, but Sairy is not feeling well. They learn that the police come around to find out who is camping out. Ma has a visit from the police and she tells them how she feels they are not treating her well. She is told to move on and if the family is still there in the morning the police will arrest them. They load up and make the dangerous journey through the desert. Noah, Tom's brother, has decided to stay at the camp and the Wilson's stay behind because Sairy is too ill to travel. While traveling through the desert Granma dies.

The family comes across a Hooverville after making arrangements to have Granma buried by the county. Tom meets a man, named Floyd Knowles, who tells Tom what life is like in a Hooverville. The police are under the control of the local landowners and they hate the people from Oklahoma most. They call them Okies and try to run them out of the camps. He also tells Tom about how little work there is in California. Connie, Rosasharn's husband, decides he can't take life on the road any longer and leaves. After a fight with the local deputy involving Floyd, Tom, and Casy, Tom and Floyd go into hiding while Casy takes the blame for the fight. The family moves on again, because they are told the camp is going to burned down that night.

The next home for the Joad family is a government run camp, which does not allow the police to enter. Tom finds work right away digging ditches. While there he and his new friends, the Wilkies, find out the big landowners are going to try to start trouble at the Saturday night dance, so the police can be brought into the camp. If there is a riot in the camp the police can then enter the camp. The Wilkies and others in the camp stop the trouble. The camp is the nicest place the family has ever camped at, but there is no work so the family has to move on.

They find work at a peach farm, which allows them to make enough money to buy food. The down side is they are brought in during a strike by the former peach farm workers. Tom discovers Jim Casy is one of the strike leaders. While talking to Casy the strikers are attacked and Casy is killed. Tom is so angered by Casy's death that he kills the man who murdered Casy. The family has to leave the following night, because they hear a posse has been formed to find and lynch Tom.

They find jobs working as cotton pickers and they live in a boxcar, which they share with the Wainwright family. Life is going well until Ruthie, Tom's youngest sister, tells a girl about Tom. Tom has been hiding out in the bushes behind the boxcars, but now he has to leave.

The rainy season hits and the boxcars are being surrounded by water. Also Rosasharn has become very ill and gives birth to a stillborn child. After the water comes into the boxcar, the family leaves and tries to find somewhere dry to stay. They find a barn, which has a boy and his father in it. The father is starving to death, but Rosasharn, who has just given birth, is able to save his life by nursing him with the mother's milk intended for her now dead child.

The Joad family endured great hardship due to the Dust Bowl, the prejudice of the local people in California, and the abuses of the big landowners. They and the others in their circumstances were victims of nature and greed. The message of the book is of hope and determination. These people no matter how bad the circumstances still persevered and still hoped for a better life.