Born on March 14, 1782, at Harts Mill, North Carolina, Thomas Hart Benton studied law at the University of North Carolina, but as a young man was attracted by opportunities in the West. He moved his family to a 40,000 acre holding near Nashville, Tennessee. There he established a plantation with schools, churches and mills. He continued his legal education and was admitted to the Tennessee bar in 1805. From 1809-1811 he served a term as a state senator.

At the outbreak of the War of 1812, General Andrew Jackson made Benton his aide-de-camp with the rank of lieutenant colonel. After the war, in 1815, Benton moved his estate to the newly-opened Missouri Territory.

With the passage of the Missouri Compromise of 1820, which made Missouri a state, Benton was elected one of its first senators. He served in the Senate from 1821 to 1851, becoming the first member of that body to serve five terms. In 1851, he was denied a sixth term by the Missouri legislature, as the polarization of the slavery issue made it impossible for a moderate Unionist like Benton to win reelection. In 1852, Benton successfully ran for the United States House of Representatives, but his opposition to the repeal of the Missouri Compromise led to his defeat in 1854. He ran for Missouri governor in 1856, but lost to Trustin Polk.

Benton died in Washington, D. C., on April 10, 1858, at the age of 76.

His descendants have continued to be prominent in Missouri life; his great-nephew, also named Thomas Hart Benton, was a famous twentieth century artist.