William Baziotes was born on June 11, 1912, in Pittsburgh, to parents of Greek origin. He grew up in Reading, Pennsylvania, where he worked at the Case Glass company from 1931 to 1933, antiquing glass and running errands. At this time, he took evening sketch classes and met the poet Byron Vazakas, who became a lifelong friend. Vazakas introduced Baziotes to the work of Charles Baudelaire and the Symbolist poets. In 1931, Baziotes saw the Henri Matisse exhibition at the Museum of Modern Art (MoMA), New York, and in 1933 he moved to that city to study painting. From 1933 to 1936, Baziotes attended the National Academy of Design.

In 1936, he exhibited for the first time in a group show at the Municipal Art Gallery, New York, and was employed by the Works Progress Administration (WPA) Federal Art Project as an art teacher at the Queens Museum of Art. Baziotes worked in the WPA's easel division from 1938 to 1941. He met the Surrealist émigrés who came to New York in the late 1930s and early 1940s, and by 1940 knew Jimmy Ernst, Matta (Roberto Sebastián Antonio Matta Echaurren), and Gordon Onslow-Ford. He began to experiment with Surrealist automatism at this time. In 1941, Matta introduced Baziotes to Robert Motherwell, with whom he formed a close friendship. André Masson invited Baziotes to participate with Motherwell, David Hare, and others in First Papers of Surrealism (1942) at the Whitelaw Reid Mansion, New York. In 1943, he took part in two group shows at Peggy Guggenheim's gallery-museum Art of This Century, New York, where his first solo exhibition was held the following year. With Hare, Motherwell, and Mark Rothko, Baziotes founded the Subjects of the Artist school, New York, in 1948. Over the next decade, Baziotes held several teaching positions in New York: at the Brooklyn Museum Art School and New York University (1949–52); People's Art Center, MoMA (1950–52); and Hunter College (1952–62).

In his lifetime, Baziotes's work was included in numerous group exhibitions that helped establish his art alongside that of other abstract painters based in New York, including shows at the Art Institute of Chicago (1947); Metropolitan Museum of Art, New York (1950); MoMA (1951, 1952); So Paulo Biennial (1953–54); Tate Gallery, London (1956); Documenta, Kassel, West Germany (1959); Walker Art Center, Minneapolis (1960); and Guggenheim Museum (1962). Baziotes died in New York on June 6, 1963. A memorial exhibition was presented at the Guggenheim Museum in 1965.