Born Harry Sinclair Lewis in Sauk Centre, Minnesota, he began reading books at a young age and kept a diary. A dreamer, at age 13 he unsuccessfully ran away from home, wanting to become a drummer boy in the Spanish-American War. He received his bachelor's degree from Yale University in 1908. He began his writing career by producing romantic poetry, then followed with romantic stories about knights and fair ladies. Lewis's first published book was Hike and the Aeroplane, which appeared in 1912 under the pseudonym Tom Graham. By 1921 he had six novels published.

Lewis was known for giving strong characterization to modern working women and for his concern with race. Some of his most famous books were Main Street and Babbitt. He was awarded the Pulitzer Prize in 1926 — which he rejected — for Arrowsmith, a novel about an idealistic doctor. Elmer Gantry was the story of an opportunistic evangelist, if not an outright charlatan; it was banned in Boston and other U.S. cities (Main Street, Babbitt, Kingsblood Royal, and Cass Timberlane have also all been banned at one time or another). In his Nobel lecture, he lamented that "in America most of us — not readers alone but even writers — are still afraid of any literature which is not a glorification of everything American, a glorification of our faults as well as our virtues," and that America is "the most contradictory, the most depressing, the most stirring, of any land in the world today."

In 1928 he married journalist Dorothy Thompson and in 1930 their son Michael Lewis was born.

Restless, Lewis traveled a lot and in the 1920s he would spend time with other great artists in the Montparnasse Quarter in Paris, France where he would be photographed by Man Ray. His last great work was It Can't Happen Here, a speculative novel about the election of a Fascist as U.S. President.

Alcohol played a dominant role in his life; he died of the effects of advanced alcoholism in Rome, Italy.