Masson was born in Balagny-sur-Thérain in France but was brought up in Belgium. He studied art in Brussels and Paris. He fought for France in World War I and was seriously injured.
Masson's early works display an interest in cubism. He later became associated with surrealism. He was one of the most enthusiastic employers of automatic drawing, making a number of automatic works in pen and ink. From around 1926 he experimented by throwing sand and glue onto canvas and making oil paintings based around the shapes so-formed. By the end of the 1920s, however, he was finding automatism rather restricting - he left the surrealist movement and turned instead to a more structured style, often producing works with a violent or erotic theme, and making a number of paintings in reaction to the Spanish Civil War (he associated once more with the surrealists at the end of the 1930s).
Under the German occupation of France during World War II, his work was condemed by the Nazis as immoral. With the assistance of Varian Fry in Marseille, Masson escaped the Nazi regime on a ship to the French island of Martinique from where he went on to the United States. Upon arrival in New York City, U.S. customs officials inspecting Masson's luggage found a cache of his erotic drawings. Denouncing them as pornographic, they ripped them up before the artist's eyes.
Living in New Preston, Connecticut his work became an important influence on American abstract expressionists. Following the war, he returned to France and settled in Aix-en-Provence, painting a number of landscapes there.