Benton was born in Neosho, Missouri into an influential clan of politicians and powerbrokers. Benton's father was a lawyer and US congressman; his great-uncle was 19th-century statesman Senator Thomas Hart Benton, after whom he was named. Benton spent his childhood shuttling between Washington D.C and Missouri. Benton rebelled against his grooming for a future political career, preferring to develop his interest in art. As a teenager, he worked as a cartoonist for the Joplin American newspaper.
In 1907 Benton enrolled at the Art Institute of Chicago, but left for Paris in 1909 to continue his art education at the Académie Julien. In Paris Benton met other North American artists such as Diego Rivera and Stanton Macdonald Wright, an advocate of Synchronism. Wright's influence gave a strong Synchronist leaning to Benton's work.
Benton returned to New York City in 1913 and continued painting. His work as a draftsman in the United States Navy in 1919 changed his style significantly. His artwork during his navy stint concentrated on realistic sketches and drawings of shipyard work and life -- a change of focus that would continue throughout Benton's career.
On return to New York in the early twenties, Benton declared himself an "enemy of modernism" and began the naturalistic and representational work today known as Regionalism. Benton taught at the Art Students League, and was active in leftist politics. He expanded the scale of his Regionalist works, culminating in the murals at the New School for Social Research in 1930-31.
In 1935 Benton left New York for a teaching job at the Kansas City Art Institute in Kansas City, Missouri. Kansas City afforded Benton greater access to the rural America then disappearing. Benton's sympathy was with the agricultural working class and the small farmer, caught in the path of the Industrial Revolution. His works often show the melancholy, desperation and beauty of small-town life.
Benton's students at the Art Institute included many of the future painters of the Midwest. His most famous student, Jackson Pollock, would go on to found the Abstract Expressionist movement -- wildly different from Benton's own style. Benton was dismissed from the Art Institute in 1941, but he remained Kansas City until his death.
For the rest of his career Benton concentrated on murals in public buildings in the Midwest, such as the Missouri State Capitol in Jefferson City. His work on the Harry S Truman presidential library in 1960 initiated a friendship that lasted for the rest of their lives. Benton died in 1975 at work in his studio, brush in hand.