Sutherland was educated at Epsom College and studied art in London (1921–25). He particularly emphasized printmaking, which he taught from 1926 to 1940 at the Chelsea School of Art. As an etcher and engraver he owes much to the Romantic painter Samuel Palmer (Palmer, Samuel) but was influenced at different times by William Blake (Blake, William), Paul Nash (Nash, Paul), Henry Moore (Moore, Henry), and Pablo Picasso. His early work was characterized by an exacting representationalism that evolved into Surrealism. He turned primarily to painting in 1935 and was represented in the 1936 International Surrealist Exhibition in London. From 1940 to 1945 he was an official war artist, and his paintings from that period provide a factual and evocative record of desolation.

Sutherland's “thorn period” began with the Crucifixion (1946) for St. Matthew's Church, Northampton, considered to be one of the most important religious paintings of the 20th century. In his late work he incorporated anthropomorphic insect and plant forms, particularly thorns, which he transformed into powerful and frightening totemic images. The hard, spiky shapes of fossils provided the theme of his large Origins of the Land (1951).

Sutherland was known, too, for his expressionistic, penetrating portraits; his painting of the writer Somerset Maugham (Maugham, W. Somerset) (1949) was the first of an impressive series. Sutherland also designed an enormous tapestry (1962) for the new Coventry cathedral. In 1960 he was elected to the Order of Merit, and in 1972 he was made a fellow of the American Academy of Arts and Letters.