Endo was born in Tokyo in 1923, but his parents moved shortly after to live in Japanese-occupied Manchuria. When his parents divorced in 1933, Endo returned to Japan with his mother to live in her hometown of Kobe. His mother converted to Catholicism when he was a small child and raised the young Endo as a Catholic. Endo was baptized in 1935 at the age of 12 and given the Christian name of Paul.

Endo studied French literature at the University of Lyon from 1950 to 1953.

His books reflect many of his childhood experiences. These include the stigma of being an outsider, the experience of being a foreigner, the life of a hospital patient, and the struggle with tuberculosis. However, his books mainly deal with the moral fabric of life. His Catholic faith can be seen at some level in all of his books, and it is often a central feature. Most of his characters struggle with complex moral dilemmas, and their choices often produce mixed or tragic results. In this his work is often compared to that of Graham Greene. In fact, Greene himself labeled Endo one of the finest writers of the 20th century.

The Shusaku Endo Literary Museum in Sotome, Nagasaki, is devoted to the writer's life and works.