After dipping into the fields of theology and education, Cox was admitted to the Ohio bar in 1853 and served in the state senate (1859–61). Appointed by the governor as one of three generals of militia (1860), he studied tactics, strategy, and military history. He subsequently raised troops for the Union and was commissioned brigadier general, U.S. volunteers. Cox took part in the West Virginia campaign (1861), and he was in supreme command of the Kanawha region from spring to August 1862. His troops were then ordered to Virginia to join General Ambrose E. Burnside's IX Corps, which he commanded during the Battle of Antietam (September). In April–December 1863 he headed the Department of Ohio, and he also participated in the Atlanta campaign (1864).

After the war, Cox was active in Republican politics, legal practice, and university administration. He was elected governor of Ohio in 1866 and served as secretary of the interior in President Ulysses S. Grant's Cabinet (1869–70), in which post he effectively opposed the patronage system. His last public office was a term in the U.S. House of Representatives, to which he was elected in 1876. Cox's extensive writings on the Civil War include Military Reminiscences of the Civil War, 2 vol. (1900).