Born in Salt Lake City, Utah, O'Higgins was raised there and in San Diego, California. In 1922 he abandoned his first career as a pianist and entered the Academy of Arts in San Diego. Within two years he'd become a student of Diego Rivera, assisting Rivera on his murals at the National School of Agriculture at Chapingo, and the Public Education Secretariat.
Like Rivera, O'Higgins became an active member of the Mexican Communist Party. He immigrated to Mexico permanently in 1924, joined the party in 1927, and maintained his party membership until 1947. His political illustrations for the Daily Worker won him a year's study at the Academy of Art in Moscow on a Soviet Scholarship in 1933.
In 1937, O'Higgins was the co-founder, with fellow artists Leopoldo Méndez and Luis Arenal, of the Taller de Gráfica Popular ("People's Graphic Workshop"). The Taller became inspiration to many politically active leftist artists; for example, American expressionist painter Byron Randall went on to found similar artist collectives after becoming an associate member. In May 1940 O'Higgins had the honor of being the only non-native Mexican artist with work included in the seminal "Twenty Centuries of Mexican Art" exhibit organized by the Museum of Modern Art.
In 1961 O'Higgins was awarded honorary Mexican citizenship for "his contributions to the national arts and education". His mural work can be seen at the Abelardo L. Rodriguez Market, Mexico City, and his 1945 "Struggle Against Racial Discrimination" is installed in Kane Hall at the University of Washington in Seattle.
Among O'Higgins' students was the American graphic designer Bob Cato.