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.

He created the fictional cities of Gopher Prairie, Minnesota and Zenith, Winnemac.

Timeline
1885 Born in Sauk Centre, Minnesota to Dr. Edwin J. Lewis and Emma Kermott Lewis.
1891 Mother dies. Father marries Isabel Warner in 1892.
1902 Attends Oberlin in Ohio.
1903-1906 Attends Yale University, serves as editor of Literary Magazine, works on cattleboats during two summers.
1906 Spends months doing odd jobs at Upton Sinclair's Helicon Hall (utopian community).
1906-1908 Works at temporary jobs, graduates Yale in 1908.
1908-1915 Travels U.S., works in New York publishing houses.
1912 Hike and the Aeroplane published (first book, a boy's adventure story).
1914 Marries Grace Hegger. Our Mr.Wrenn published.
1917 The Job and The Innocents published. Son, Wells, born.
1919 Free Air published.
1920 Main Street published, first major commercial success.
1922 Babbitt.
1925 Arrowsmith.
1926 Mantrap. Awarded Pulitzer Prize for Arrowsmith but refuses it. Father dies.
1927 Elmer Gantry.
1928 The Man Who Knew Coolidge. Divorces Grace Hegger, marries journalist Dorothy Thompson.
1929 Dodsworth.
1930 Son Michael born. Awarded Nobel Prize in Literature on November 5 (first American to be so honored).
1933 Ann Vickers
1934 Work of Art. Assists Sidney Howard in adapting Dodsworth to the stage.
1935 It Can't Happen Here and Selected Stories.
1936-1942 Writes several plays and acts in a few of them.
1938 The Prodigal Parents.
1940 Bethel Merriday. Teaches briefly at University of Wisconsin.
1942 Divorces Dorothy Thompson.
1943 Gideon Planish.
1944 Lt. Wells Lewis killed by sniper in Piedmont Valley, France (near Alsace-Lorraine) during WW II.
1945 Cass Timberlane.
1947 Kingsblood Royal.
1949 The God Seeker.
1951 Dies in Rome of heart disease. He is buried in Greenwood Cemetery, MN. World So Wide published posthumously.