Born in Atlantic City, New Jersey, Lawrence moved to Harlem, New York with his mother, sister, and brother in the 1920s, during what is now known as the Harlem Renaissance. He studied art at the Harlem Art Workshop 1934-36, and won a scholarship to the American Artists School, New York 1937-39. Lawrence worked as an artist under the Federal Art Project, and in 1939 had his first solo exhibition. A Social Realist, he used his art to universalize the plight of the African-Americans. His multi-canvas series usually told the story of an African-American historical event or hero, such as the 30-panelled Harriet Tubman Series (1939-40) concerning the founder of the Underground Railroad (a network for escaped slaves). The distinctive flat surfaces of his paintings were created with gouache, an opaque watercolour, and tempera, a mixture of pigment and a binder.

Lawrence taught art at the Pratt Institute in New York 1958-65, and also at the University of Washington, Seattle, from 1970. In 1993 he wrote and illustrated Harriet and the Promised Land, a children's book about Harriet Tubman. Other African-American artists inspired by the Harlem Renaissance include Aaron Douglas and Romare Bearden.