During the War of 1812, (1812, War of) Cass rose from the rank of colonel of volunteers to brigadier general in the regular army. He was governor of Michigan Territory from 1813 to 1831. As secretary of war in President Andrew Jackson (Jackson, Andrew)'s cabinet (1831–36), he directed the conduct of the Black Hawk and Seminole wars. For the next six years, he served as minister to France.

As a member of the U.S. Senate (1845–48, 1849–57), Cass became a leader of the 1846 bloc demanding the “reannexation” of all the Oregon country south of latitude 54°40′ N or war with England. He supported President James K. Polk (Polk, James K.)'s administration during the Mexican War (Mexican-American War) (1846–48) and opposed the Wilmot Proviso, an antislavery proposal applying to land acquired from Mexico.

In the 1848 presidential campaign, Cass was the Democratic nominee but was defeated by the Whig candidate, Zachary Taylor (Taylor, Zachary). He served as secretary of state (1857–60) under President James Buchanan (Buchanan, James), but he retired from the post when the president refused to take a firmer stance against the secession of the Southern states.