After studying art in Sicily, Guttuso moved to Rome in 1931 and took part in the Quadrennial with two works. He developed his artistic vision in contact with the painters of the Roman School, especially Mario Mafai and Corrado Cagli.

Attracted by the lively cultural scene in Milan, he took part in the exhibition of the Group of Sicilian Painters at the Galleria del Milione in 1932, where he also exhibited work in 1934. He returned to Milan during his military service between 1935 and 1937 and came into contact with Renato Birolli, Aligi Sassu, Raffaele De Grada and Ernesto Treccani of the Corrente movement, which he joined, thus playing an important role as a link between Rome and Milan.

He came to prominence on the Italian art scene in 1942 at the Bergamo Prize, where he was placed second and came under attack from the artistic establishment for his expressionistic use of colour and a synthesis of form and volume derived from the study of Picasso’s works. He took part in the Italian Resistance and produced works of a raw expressionist character as protests against Nazi violence in the same period. The post-war years saw the start of intense and lasting involvement in exhibitions at the international level with a vast repertoire including social themes, still life, landscape and intense portraits with rich autobiographical and existential overtones.

He founded the Nuova Secessione Artistica Italiana, later named the Fronte Nuovo delle Arti, together with Renato Birolli, Emilio Vedova and Ennio Morlotti, establishing himself as a leader of the realist movement with works of great social commitment in line with the cultural policies of the Italian Communist Party, of which he became an active and authoritative member. After the group broke up in 1950, he continued to address the same subjects together with depictions of aspects of the society of consumption and affluence. He was also active as a writer, set designer and illustrator in his maturity.