In 1936 Lawrence was painting scenes of Harlem interiors and street life, using the flat style that was to become his lifelong trademark. During the next year he began his first narrative series with texts: 41 panels on the life of Toussaint Louverture, the liberator of Haiti. Some of Lawrence's Harlem scenes were included in a 1937 group exhibition of the Harlem Artists Guild, and then featured in his first solo exhibition, which was held in the next year at the Harlem YMCA. After a New York showing at the De Porres Interracial Center, his Toussaint series traveled to the Baltimore Museum of Art in 1939 for the exhibition Contemporary Negro Art.

Lawrence's first teaching job came in the summer of 1946 when Joseph Albers persuaded him to join the Summer Institute of his experimental arts school, Black Mountain College, in Asheville, North Carolina. In the summer of 1954 Lawrence taught at the Skowhegan School of Painting and Sculpture in Maine, and in the fall of 1955 he became an instructor at Pratt Institute in Brooklyn, where he stayed until 1970. In that year he was appointed visiting artist at the University of Washington in Seattle, and in 1971 he became a full professor there, a position which he held until his retirement in 1986. He also held several visiting positions:
Skowhegan in the summers, 1968-1972; Brandeis University as artist-in-residence in the spring of 1965; the New School for Social Research as part-time instructor, 1966-1969; the Art Students League, 1967-1969; and California State College at Hayward, 1969-1970. In 1961 Lawrence began reworking earlier themes as prints.

The 60-panel Migration Series, organized by the Phillips Collection, circulated in 1993-1995. Murals on the themes of sports and work are on the walls of Kingdome Stadium in Seattle, and the New York City subway system. Lawrence was honored by President Jimmy Carter in 1980, and he was inducted into the American Academy of Arts and Letters in 1994. In 1990 he received the National Medal of Arts from President George Bush.