The Bridge of San Luis Rey tells the story of several interrelated people who die in the collapse of an Inca rope bridge in Peru, and the events that lead up to their being on the bridge. A friar who witnesses the accident then goes about inquiring into the lives of the victims, seeking some sort of cosmic answer to the question of why each had to die.

The Bridge of San Luis Rey won the 1928 Pulitzer Prize for the Novel, and remains widely acclaimed as Wilder's most famous work.[citation needed] In 1998, the book was rated number 37 by the editorial board of the American Modern Library on the list of the 100 best 20th-century novels. Time magazine included the novel in its TIME 100 Best English-language Novels from 1923 to 2005.

From the earnings of The Bridge of San Luis Rey, in 1930 Wilder built a house for his family in Hamden, Connecticut. His sister Isabel lived there for the rest of her life. This became his home base, although he traveled extensively and lived away for significant periods. He died in this house on December 7, 1975, of heart failure. He was interred at Mount Carmel Cemetery, Hamden, Connecticut.