Diego Rivera was, along with David Alfaro Siqueiros and Jose Clemente Orozco, one of the "Big Three" muralists of the Mexican Mural Movement. The movement began in the wake of the 1910 Mexican political revolution that overthrew the long-standing reign of President Porfirio Diaz and set up a pseudo-socialist government. The political climate of the time was felt in the murals of all three as they sought to express the role of the people in Mexican history, over that of the wealthy hacendado class that had ruled so long.

His best known works include those created at the National Preparatory School, the building of the Ministry of Education, Chapingo University, the National Palace in Mexico City, and his "Man at the Crossroads" mural in Rockefeller Center, executed for the Rockefellers in 1933. The Crossroads mural was particularly controversial due to Rivera's earlier criticism of the class of wealthy American industrialists that were typified by the Rockefeller family. River surprised many, however, by including a portrait of Lenin in the mural. The Rockefellers ordered him to cease work on the mural and soon destroyed it in response to the socialist message implied by the portrait.

Rivera is generally credited with having given a voice to the "monumental, useful, people's art" that expressed the feelings behind the revolution.