Them explores the complex struggles of American life through three down-on-their-luck characters—Loretta, Maureen and Jules—who are attempting to reach normality and the American dream through marriage and money.
The story begins with Loretta Botsford and her brother Brock as teenagers, living in a "fair-sized city on a midwestern canal", in the 1930s. Loretta falls in love with Bernie Malin, and sleeps with him. Later in the night, Brock shoots Bernie in the head, and Bernie dies suddenly. Loretta runs away, and meets Howard Wendall, an older cop to whom she confesses the death of Bernie Malin. They later marry, and she bears her son Jules (who was hinted to be Bernie Malin's son). Loretta and Howard live close to Mama and Papa Wendall's house, on the south side of town. Soon after the birth of Jules, Howard is busted for taking money from prostitutes. The Wendalls move into the country house with Howard's family where Loretta bore her daughters Maureen, and Betty.
When World War II breaks out, Howard leaves his family to fight in Europe. Meanwhile, Jules grows up to be a fast, energetic child who hangs around older children, and is never still. Maureen is a quiet, shy, delicate girl, while Betty is a smart aleck. Jules as a child is fascinated by fire; when he burns down a deserted barn and when a plane crashes in Detroit.
Loretta decides to move to Detroit with Jules, Maureen and Betty while Howard is still at war. Jules takes on the role of the "bad boy" who hangs out with kids who steal from stores and smoke at school. Many conclude that Jules will not live past twenty. Soon Jules is expelled from the Catholic school and sent to a public school away from his sisters.
As time progresses, Jules becomes more involved in petty theft but always has hopes for a better life. He falls passionately in love with a rich girl, Nadine, from the suburbs whom he helps to run away from home to Texas. She abandons him in a hotel, however, when he becomes ill, stealing his car and money.
After Howard dies in a work accident, Loretta remarries and relies more and more on Maureen to run the household. Feeling the desire to escape, Maureen turns to prostitution to build an escape fund. When her step-father discovers her secret, he savagely beats her, resulting in his jail sentence, Loretta's divorce, and Maureen suffers a nervous breakdown for over a year. She gradually recovers with the care of Loretta's brother Brock, who has unexpectedly returned and the letters of Jules, who slowly drifts back North.
Some time later, Jules is doing better in business working for his uncle when he reconnects with Nadine. She has married, but they initiate an affair. However, she has mental problems and shoots him. Jules survives, but has lost all his drive. Maureen has moved out and is working as a typist and taking night classes. She sets her sights on her professor, a married man, and they begin an affair. When Maureen coolly tells her mother of her plans to become a housewife, Loretta is incensed.
After his recovery, Jules is a defeated man, maintaining several affairs. He rapes a girl and later pimps her out, and he becomes involved with a group of intellectual radicals. He is present at the 1967 Detroit riots, where Loretta's apartment is among the buildings burned. In the chaos, Jules sinks to a new low when he finally commits murder.
Later, Jules visits Maureen, who has isolated herself from the rest of her family in Dearborn with her husband and is expecting a child. Loretta is surviving while Jules plans to try his fortunes in California.