Benton was the child of a distinguished political family. He was named for his famous forebear who represented Missouri (and the West in general) in the United States Senate from 1821 to 1851. His father, after public service in his home state, was elected to the United States House of Representatives, serving four terms, 1897-1905. The family was resident in Washington, D. C. for this period, and in addition to attending public school in the District, he had some classes at the Corcoran Gallery of Art. Back in Missouri, Benton worked briefly as a cartoonist for the Joplin, Missouri, American, before going to Chicago where he studied at the school of the Art Institute in 1907-08, intending to become an illustrator. However his ambition soon changed to becoming a serious painter; in 1908 he went to Paris where he studied at the Académie Julian and the Académie Collarossi, and absorbed the modernist styles and attitudes of the Paris School.
He was briefly in Missouri on his return to America in 1911, before settling in New York, which remained his base to 1935. Initially, Benton worked in several avant garde modes, particularly the Synchromy style of his friends Morgan Russell and Stanton Macdonald-Wright; the first significant exhibition of his work was in the 1916 Forum Exhibition of Modern American Painters, held at the Anderson Galleries, New York. Early in the 1920s, however, he turned to the realist style, which became characteristic of his mature work. By the mid-20s Benton was at work on American Historical Epic, the first of a number of mural cycles he would execute expressive of a strongly personal interpretation of Americanist themes. While American Historical Epic was personally motivated, Benton first major commissioned mural, America Today, for the New School of Social Research, New York, completed 1930, would also be the first to engage him in controversy--both political and artistic--on which he apparently thrived.
Throughout his life Benton produced easel paintings, as well as a notable series of lithographs, and enjoyed frequent one-man exhibitions in New York galleries and other American cities. But it was in mural painting that he expanded on his view of American life and history, and that the great regard for his art is centered. Among the more famous (in their time, called infamous by some) are The Arts of Life in America for the Whitney Museum of American Art, New York, 1932; Social History of the State of Indiana for the Indiana Pavilion at the Century of Progress International Exposition, Chicago, 1933; A Social History of the State of Missouri for the Capitol Building, Jefferson City, Missouri, 1936; Abraham Lincoln for Lincoln University, Jefferson City, 1954; Independence and the Opening of the West for the Harry S. Truman Library, 1962.
Benton became a regular member of the faculty of the Art Students League, New York, in 1926, a post which provided him with a steady income. In 1935, simultaneously with receiving the commission for the Missouri State Capitol murals, he was invited to head the painting department of the Kansas City (Missouri) Art Institute, and removed permanently to Kansas City where he lived for the rest of his life.
Benton's international fame is attested to by the many awards that he recieved. Among these were a gold medal for decorative painting from the Architectural League of New York, 1933; the Diamond Jublilee Gold Medal of the National Arts Club, 1974; honorary memberships in the Argentine Academia Nacional de Bellas Artes, 1945, the L'Accademia Fiorentina delle Arti del Disegno, Florence, 1949; and honorary degrees from the University of Missouri, 1948, Lincoln University, 1957, and the New School for Social Research, 1968. Benton was elected to the National Academy of Arts and Letters in 1962, resigned in 1965, and was reelected the following year.