Five people are killed when a heavily-traveled rope bridge in Peru collapses. Brother Juniper, a Franciscan friar, witnesses this event and this sets him on a quest: Who were each of these individuals? Why do unfortunate events happen to innocent or undeserving people? What led to these people being on the bridge at the fateful moment?

While many view this novel as a serious reflection on life, death, and love, this narration highlights Wilder's tongue-in-cheek stance, suggesting the author used humor, irony, and even sarcasm to examine faith, fate, and chance. Throughout the story, Wilder unleashes gentle sarcasm on the Catholic Church, the Peruvian administration, and Spanish American culture in general.

In 1998 The Bridge of San Luis Rey was selected by the editorial board of the American Modern Library as one of the 100 best novels of the twentieth century.