Born in Hope, Vermilion County, Illinois, Van Doren was the son of a country doctor and was raised on the family farm. He earned a bachelor of arts from the University of Illinois at Urbana-Champaign in 1907 and a doctorate from Columbia University in 1911 and continued to teach there until 1930. He was a world federalist and once said, "It is obvious that no difficulty in the way of world government can match the danger of a world without it".

Van Doren's study The American Novel, published in 1921, is generally credited with helping to re-establish Herman Melville's critical status as first-rate literary master.

From 1912 to 1935, Van Doren was married to Irita Bradford, editor of the New York Herald Tribune book review. He married Jean Wright Gorman in 1939, but divorced in 1945.

Van Doren died in Torrington, Connecticut.

A residence hall at the University of Illinois at Urbana-Champaign is named after Carl Clinton Van Doren.