Born Philip Goldstein on 27 June 1913 in Montreal, Canada, Guston moved with his family to Los Angeles, California, in 1919. In 1927 he enrolled at the Manual Arts High School, Los Angeles, where he became friendly with his fellow student Jackson Pollock. In 1930 Guston was awarded a year's scholarship to the Otis Art Institute, Los Angeles, but left after three months. He held his first solo exhibition in 1931 at Stanley Rose's bookshop and gallery in Los Angeles.

Guston travelled to Mexico in 1934 seeking mural work with David Siqueiros and executed a mural in the Emperor Maximilian's former summer palace in Morelia. In the winter of 1935–1936, he moved to New York where he joined the mural section of the Works Progress Administration (WPA) Federal Art Project. It was at this time that he began using the name Philip Guston. He received his first major mural commission in 1939 for the façade of the WPA building at the New York World's Fair.

He resigned from the WPA in 1940, moved to Woodstock, New York, and began to concentrate on easel painting. In 1945 he held his first solo exhibition in New York at Midtown Galleries. In 1948 he was awarded the Prix de Rome from the American Academy in Rome and spent a year travelling in Italy. He held his first solo exhibition of abstract paintings at the Peridot Gallery, New York, in 1951. In 1958 his work was included in the exhibition The new American painting, organised by the International Council at the Museum of Modern Art, New York, which travelled throughout Europe. In 1962 a major retrospective of his work was organised by the Solomon R. Guggenheim Museum, New York, which also toured internationally.

Guston continued to work in an abstract idiom until the mid 1960s, then, after an intense period of drawing, he began painting figurative works again in 1968–1969, showing them for the first time in a solo exhibition at Marlborough Gallery, New York, in 1970. The artist then exhibited regularly at David McKee Gallery, New York, from 1974. From 1973 to 1978 he held the position of professor of art at Boston University. In May 1980 an important retrospective of his work was organised by the San Francisco Museum of Modern Art, which toured to venues in the United States. The artist died, in Woodstock, on 7 June 1980, three weeks after attending the opening of his retrospective in San Francisco. Another retrospective was held in 2003–2004 in Fort Worth, San Francisco; the Metropolitan Museum of Art, New York; and the Royal Academy of Arts, London.