Born in the village of Sauk Centre, Minnesota,Lewis began reading books at a young age and kept a diary. He had two siblings, Fred (born 1875) and Claude (born 1878). His father, Edwin J. Lewis, was a physician and a stern disciplinarian who had difficulty relating to his sensitive, unathletic third son. Lewis's mother, Emma Kermott Lewis, died in 1891. The following year, Edwin Lewis married Isabel Warner, whose company young Lewis apparently enjoyed. Throughout his lonely boyhood, the ungainly Lewis — tall, extremely thin, stricken with acne and somewhat popeyed — had trouble gaining friends and pined after various local girls. At the age of 13 he unsuccessfully ran away from home, wanting to become a drummer boy in the Spanish-American War.
Lewis died in Rome on January 10, 1951, aged 65, from advanced alcoholism. His cremated remains were buried in Sauk Centre. A final novel, World So Wide (1951), was published posthumously.