Narrated in the third-person by an unnamed omniscient narrator, The Last White Man opens with the protagonist, Anders, waking up to discover that his white skin has turned brown. He looks at his own reflection with a murderous rage, smashing his bathroom mirror. For a week, he calls in sick to work at the gym where he is a personal trainer. He only goes out for groceries.
Eventually, Anders calls Oona, an old flame from high school who has recently moved back to their unnamed town to care for her mother following her twin brother's suicide. Oona, a yoga instructor, is reluctant to get sucked in to Anders's distressed state, but she goes to his small house, smokes pot with him as he tears up, and then has sex with him. Feeling awkward, she leaves in the middle of the night. In the morning, her mother, who gets swept up in right-wing conspiracy theories, tells her that "our people" are changing. The world looks increasingly dangerous to Oona's mother, but Oona dismisses her concerns.
Oona avoids Anders for a week, responding to his messages but not making plans to see him out of discomfort with his situation. Anders reveals his change to his father, who grieves the change but welcomes his son inside. Anders returns to work at the gym; his white boss says he would have killed himself if he had changed color. When the news reports on more people changing, Oona gets together with Anders again. The news also reports on people who have changed killing themselves.
Oona's mother embraces theories about a plot against "their kind." She wants to stockpile supplies. Oona gets drawn into the panic, wondering if her mother might be right. Anders's father gives his son a rifle to protect himself against white militants who start harassing "dark people" and running them out of town. Anders conceals himself in public, wearing a hoodie, sunglasses, and gloves. Having gotten over some of her aversion, Oona has sex with Anders again, passionately and languidly.
Public violence escalates as increasingly more people change color. When riots erupt, both Anders's and Oona's workplaces close temporarily. Anders keeps his rifle close to him as he waits in his home. Oona's mother insists that it's not the white militants who are the aggressors, but the dark people. She says that the remaining pale people need protection from being changed. When militants show up at Anders's house, he opens the door with his rifle ready. He stares them down, but later he flees nonetheless, moving into his father's house. Oona, meanwhile, hunkers down at her mother's. The power goes out, but then returns at the end of the day. Oona experiments with putting on brown makeup, which she orders online. She likes how she looks but washes it off at the end of the evening.
After spending much of the winter inside his home, Anders isn't sure he can trust his neighbors. Oona comes over and says the streets aren't as violent anymore. With more and more dark faces appearing out in public, the mood shifts. Oona's mother's online forums discuss miracle cures that can reverse the color change. People die or get sick from taking them. Meanwhile, Anders's father is in increasingly worse pain. Anders risks going out so he can buy his father end-of-life drugs from a hospice employee.
One night, Anders comes to Oona's to have sex. Oona's mother opens the door and vomits when she sees them together. Soon after, Oona changes color herself. She feels both melancholy and a sense of optimism, as though she has escaped her former skin. Oona's mother forces herself to accept her daughter's transformation, but struggles. Meanwhile, most people in the town and country have changed color.
Oona's mother is among the last people to change color. She engages with the same community she used to online; many of them post photos of their new selves. When Anders's father dies and has an open-casket funeral, he is the only pale person in the room. With his burial, the last white man in town is gone.
Oona's mother reads new theories that attempt to differentiate changed people and those who were always dark; the originally dark people are spoken of as savages. Oona's mother steadily stops paying attention to these theories. She begins going out in public, growing used to her changed color. She embraces Anders and Oona's relationship to make up for her earlier revulsion.
Time passes quickly as Anders and Oona move into Anders's father's house—Anders's childhood home. They renovate and repaint, then have a daughter—who is dark-skinned from birth. Oona's mother talks often about the white past until her granddaughter tells her to stop. At the end of the novel, Anders and Oona's granddaughter is a teenager. She spends all night out on the town and comes home seeking comfort from her parents, climbing into bed with them.
