In Oklahoma, Tom Joad, imprisoned for killing a man in a brawl, is paroled and reunited with Jim Casy, a former preacher who has given up preaching and decided sin is just stuff that people do. Tom and Casy return to the Joad's farm and find the family preparing to leave for California. They have lost their farm, and there are flyers promising endless work in the paradisiacal California. They cling to California—or their dreams of it—as the only way to recover their lost lives. So, soon the entire Joad family—Grampa, Granma, Ma, Pa, the children Noah, Tom, Al, Rose of Sharon (who is pregnant), Ruthie, and Winfield, Rose of Sharon's husband Connie, Casy, and their dog—sets out on their journey for California in a rickety truck that Al and Tom struggle to keep running.

As they travel along Highway 66, they meet Ivy and Sairy Wilson, a couple heading to California, and they travel together for a while until near the border of California, when Sairy gets too sick to travel. During this last leg of the journey, Granma gets sick and soon dies. The closer they get to California, the more they hear rumors that the Promised Land is no paradise: they hear the migrants are suppressed and forced to work for barely enough money to feed themselves. Grandpa dies of an aneurism.

When they finally arrive, the worst of the rumors prove true. They stay in a Hooverville, a collection of homeless migrants who have set up a camp. Their experience is miserable. Work is scarce, though Tom is able to find a small job. The sheriffs of California abuse the migrants and stir up a fight in the Hooverville. Tom interferes and attacks a sheriff, but Casy turns himself in and tells them he started the fight. The Joads leave the camp, and later that night the deputies return and burn it to the ground. From there, they travel to the federal government's Weedpatch Camp where migrants are allowed to care for themselves and where they prohibit any deputies from entering. There the Joads have a nice place to live, hot water, and are provided food in return for work. Troublemakers try to stir up a fight at one of the camp's dances so the deputies can enter, but Tom learns of the plot and helps thwart it. In the end, though, a month goes by and they can find almost no work so they leave the comfort of the camp.

They find a job picking fruit, and outside of the farm, Tom once again meets Casy who was let out of jail. Casy is leading a strike against the farm owners' inhumane, low wages, and he convinces Tom it is only through uniting against the farm owners that the migrants will survive. While Tom is there, several deputies arrive and attack Casy, hoping to end the strike by killing him. Casy is killed, but Tom retaliates and kills one of the deputies, so he is forced to go into hiding. The family leaves that camp and finds another job picking cotton . They live in a boxcar near the farm. Ruthie, the young Joad daughter, gets into a fight with another girl at the camp and reveals her brother has killed two men and is now hiding. Ma, in fear for Tom's safety, insists he go away, and he tells her he is going to follow in Casy's footsteps and try to unite the migrant workers.

The cotton is soon picked, and there is little other work to be found. Then, when things seem as bad as they can get, there comes an endless rain and a terrible flood destroying all of the few remaining crops. While the rain pours, Rose of Sharon goes into labor but delivers a stillborn baby. Sick and cold, the Joads abandon their flooded truck and take shelter in a barn. There they find a starving father and his son. The father had for days been giving all of his food to his son, and he is now too ill to keep any solid food down. The novel closes with Rose of Sharon sending everyone out of the barn and suckling the starving man.