Tarkington studied at Purdue and Princeton universities but took no degree. A versatile and prolific writer, he won early recognition with the melodramatic novel The Gentleman from Indiana (1899), reflecting his disillusionment with the corruption in the lawmaking process he was to observe firsthand as a member of the Indiana legislature (1902–03). His immensely popular romance Monsieur Beaucaire (1900) he later adapted for the stage. His humorous portrayals of boyhood and adolescence, Penrod (1914), Penrod and Sam (1916), Seventeen (1917), and Gentle Julia (1922), became young-people's classics. He was equally successful with his portrayals of Midwestern life and character: The Turmoil (1915); The Magnificent Ambersons (1918; filmed 1941 by Orson Welles), and The Midlander (1924), the last two combined as Growth (1927); and The Plutocrat (1927). Alice Adams (1921), a searching character study, is perhaps his most finished novel. He continued his delineations of female character in Claire Ambler (1928), Mirthful Haven (1930), and Presenting Lily Mars (1933) and wrote several domestic novels in his later years. He also wrote many plays.

Tarkington was one of the most popular American novelists of the early 20th century: from The Two Vanrevels (1902) to Mary's Neck (1932) his novels appeared on annual best-seller lists nine times. Tarkington possessed an informal, charming style and a gift for characterization. His critical vision was obscured by a tendency toward sentimental melodrama, however.