After two terms in the U.S. House of Representatives (1812–16), McLean was appointed a judge in the Supreme Court of Ohio, a position he resigned in 1822 to become commissioner of the General Land Office under Pres. James Monroe. In 1823 he was named postmaster general and became noted for his efficiency and nonpartisanship in that office. After Pres. Andrew Jackson took office McLean resigned in protest over Jackson's open advocacy of the spoils system of political patronage, which undermined McLean's recent reforms. Jackson thereupon appointed him an associate justice of the U.S. Supreme Court.

In Dred Scott (Dred Scott decision) v. Sandford (1857), McLean insisted, in a minority opinion, that a slave became free when his owner took him into a state where slavery was not legally established. In McLean's view, a free black was a citizen and thus was able to sue, in a case involving diversity of state citizenship, in a federal court. His position was reflected in the Fourteenth Amendment to the U.S. Constitution (1868).