Corwin served three years in the Ohio Assembly before turning to national politics in 1831. Identified with the Whig Party, he was a member of the House of Representatives (1831–40), governor of Ohio (1840–42), and U.S. senator (1845–50).

In 1847 Corwin made a memorable speech denouncing the Mexican War (1846–48) as unjust and predicting a civil war in the United States as one of its effects. After serving as secretary of the Treasury (1850–53) under President Millard Fillmore, he returned to the House of Representatives (1859) as a Republican. During the secession crisis of 1861 he acted as chairman of the congressional Committee of Thirty-Three, which sought a compromise between North and South. In his last public office, as U.S. minister to Mexico (1861–64), he was instrumental in preventing Southern agents from gaining support from the Mexican government.