On Beauty centres around two families and their different yet increasingly intertwined lives. The Belsey family consists of university professor Howard, a white Englishman and Rembrandt scholar; his African-American wife Kiki; and their children, Jerome, Zora, and Levi. They live in the fictional university town of Wellington, outside Boston. Howard's professional nemesis is Monty Kipps, a Trinidadian living in Britain with his wife Carlene and children Victoria and Michael.
The Belsey family defines itself as liberal and atheist, and Howard in particular is furious when his son Jerome, lately a born-again Christian, goes to work as a summer intern with the ultra-conservative Christian Kipps family. After a brief and badly ending relationship with Victoria, Jerome returns home. However, the families are again brought closer nine months later when the Kipps family move to Wellington, and Monty begins work at the university. Meanwhile, the Belsey family is dealing with the fallout of Howard's affair with colleague and family friend Claire.
Carlene and Kiki become friends despite the tensions between their families. The women bond over Maitresse Erzulie, a painting by Haitian Hector Hyppolite in Carlene's library. Carlene tells Kiki that she purchased the painting in Haiti prior to meeting Monty. The women see each other twice more before Carlene dies of cancer, having kept her illness from her family. The Belseys attend Carlene's funeral in London, where Howard has sex with Victoria, now his student and with whom he had an ongoing flirtation. While reviewing Carlene's will, the Kipps family discover that Carlene intended Maitresse Erzulie be left to Kiki. Believing Carlene to have been of unsound mind, Monty instead hangs the painting in his university office.
The rivalry between Monty and Howard increases as Monty challenges the liberal attitudes of the university on issues such as affirmative action, which comes to a head when both men debate the topic before students and staff. Monty's academic success also highlights Howard's inadequacies and failure to publish a long-awaited book. Zora and Levi become friends with Carl, a young African-American man of a lower-class background. Zora uses him as a poster-child for her campaign to allow talented non-students to attend university classes. For Levi, Carl is a source of identity, as a member of what Levi considers a more "authentic" black culture.
Levi quits his retail job due to its poor employee treatment. Struggling with his mixed-race identity, he befriends and works for a group of Haitian men who sell counterfeit merchandise on Boston streetcorners. Levi views them as the "essence of blackness,"[5] while remaining self-conscious of being seen in public with members of the Haitian population of Wellington. Levi's friend Chouchou claims that Monty bought Haitian artwork from peasants for very little money, and Levi and Chouchou steal the Hyppolite painting from Monty's office as part of a campaign against anti-Haitian injustice. Upon discovering the stolen painting in Levi's room, Jerome finds a note from Carlene gifting the painting to Kiki.
Meanwhile, Zora and Howard arrive home, and Zora reveals to Howard that she knows about two crucial affairs: his with Victoria, and Monty’s with another student. Zora tells her mother about the affair with Victoria.
The final chapter depicts the Belseys in an early stage of separation. In the final scene, Howard fails to deliver a potentially career-reviving lecture. Instead, he smiles at his wife in the audience and she returns the smile, under a projection of Rembrandt's depiction of his own wife in Hendrickje Bathing, 1654.
