Set in colonial Peru in the early 18th century, The Bridge of San Luis Rey interweaves the stories of five people who die when an ancient rope bridge breaks and sends them plunging into a gulf. The book opens with an account of how a Franciscan monk named Brother Juniper witnessed the accident and spent his subsequent years amassing evidence to explain why God singled out these five for premature death. Wilder then narrates their life stories leading up to the moment they crossed the bridge. The Marquesa de Montemayor is a rich, ugly, elderly aristocratic woman who lives only for the well-being of her child, a haughty beauty named Clara who has recently married and moved to Spain. The Marquesa devotes herself to writing long, beautifully meditated letters to Clara and performing elaborate superstitious rituals on her behalf. She finally finds peace from her unrequited maternal love two days before she and her servant girl Pepita cross the bridge. Esteban is an identical twin orphan who loves his brother Manuel with an all-consuming, single-minded, wordless ferocity and is deeply wounded when Manuel falls in love with the beautiful, vain actress Camila Perichole, and then is devastated when Manuel dies soon after. On the brink of suicide, Esteban agrees to embark on a long voyage with a sea captain he respects, but on the way to Lima he happens to cross the bridge at the precise wrong moment.

The final narrative tells of the adventures of Uncle Pio, a wise and wily old man who has dedicated the better part of his life to guiding the stupendous acting career of Camila Perichole. Uncle Pio looks on with amusement and dismay as Perichole becomes the toast of Lima, enters into a profitable love affair with the Viceroy of Peru, and finally renounces her stage career for the life of a great lady. When Camila contracts small pox and loses her looks, she shuts herself away in the country with her sickly young son Don Jaime. Pio convinces her to let him take Don Jaime to Lima so that he can educate the boy as a gentleman. Pio and Don Jaime die with the others on the doomed bridge. In the last chapter the novel returns to Brother Juniper, who finally completes his vast tome about the five victims of the bridge collapse: for his efforts he is condemned as a heretic and burned, along with his book, on Lima's central square.