A simple, hulking dentist finds his life unraveling when a sudden windfall of money triggers an obsessive, destructive greed in his wife. McTeague, a man of limited intellect and brute strength, operates an unlicensed dental practice in San Francisco until his marriage to Trina Sieppe introduces a volatile element of avarice into their lives. As Trina wins a lottery prize, the couple's relationship shifts from mundane domesticity to a toxic cycle of suspicion, hoarding, and physical violence. The narrative follows their inevitable decline, moving from the cramped urban quarters of the city to the harsh, unforgiving landscape of Death Valley. Norris employs a third-person omniscient perspective to observe the characters as if they were subjects in a biological experiment, emphasizing the influence of heredity and environment on human behavior.

Readers and critics frequently identify this work as a definitive example of American naturalism, noting its unflinching look at the darker impulses of human nature. Discussion often centers on the stark contrast between the mundane, gritty reality of the city and the final, brutal confrontation in the desert. Many observers highlight the author's clinical, detached prose style, which mirrors the scientific observation of human degeneration. The novel is often analyzed for its commentary on the corrupting influence of money and the fragility of social structures. Scholars frequently point to the influence of European naturalists on the author's approach to character development and environmental determinism.