The son of a Presbyterian pastor, Charles Sackett Sydnor was the oldest of five children. After graduating from Hampden-Sydney College, he received a Ph.D. from Johns Hopkins University. He taught history and political science at Hampden-Sydney before accepting an offer to become chair of the history department at the University of Mississippi in 1925. In 1936, he became an associate professor of history at Duke University, where he was eventually named the James B. Duke Professor.