John Middleton Clayton was born in 1796 in Dagsborough, Delaware. He graduated from Yale College in 1815, studied the law at Litchfield (Connecticut) Law School, was admitted to the Delaware state bar in 1819, and then established a law practice.

Clayton served in the Delaware House of Representatives from 1824 to 1826 before serving two years as Delaware's secretary of state. By 1829, he was in the United States Senate; he won reelection in 1834 but resigned the seat in 1836 to become chief justice of the Delaware Supreme Court, a position he held for three years. In 1840, he joined the Whig Party, campaigned for Whig presidential candidate William Henry Harrison, and was elected to the United States Senate in 1844.

Clayton remained in the Senate from 1845 to 1849, at which time President Zachary Taylor nominated him as secretary of state. When Taylor died in 1850, Clayton resigned his cabinet post and three years later returned to the Senate. He served there until his death in 1856.