William Baziotes was born June 11, 1912, in Pittsburgh, Pennsylvania, to parents of Greek origin. He grew up in Reading, Pennsylvania, where he worked at the J. M. Kase & Company, a factory specializing in stained glass, from 1931 to 1933, running errands and learning how to antique glass. He also took evening sketch classes and met the poet Byron Vazakas, who became his 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 in New York, and in 1933 he moved there 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 in New York, and was employed by the Works Progress Administration Federal Art Project as an art teacher at Queens Museum. Baziotes worked in the easel painting division of the WPA from 1938 to 1941. He met the Surrealist émigrés in New York in the late 1930s and early 1940s, and by 1940 knew Jimmy Ernst, Roberto Matta, and Gordon Onslow-Ford, and began to experiment with Surrealist automatism. In 1941, Matta introduced Baziotes to Robert Motherwell, who became a close friend. André Masson invited Baziotes to participate with Motherwell, David Hare, and others in the 1942 First Papers of Surrealism exhibition at the Whitelaw Reid Mansion in New York.

In 1943, Baziotes took part in two group shows at Peggy Guggenheim’s museum-gallery Art of This Century in New York, where his first solo exhibition was held the following year. Together with Hare, Motherwell and Mark Rothko, Baziotes founded The Subjects of the Artist School in New York in 1948. Over the next decade, Baziotes held a number of teaching positions in New York: at the Brooklyn Museum Art School and at New York University, from 1949 to 1952; at the People's Art Center at the Museum of Modern Art, from 1950 to 1952; and at Hunter College from 1952 to 1962. Baziotes died in New York on June 6, 1963. A memorial exhibition of his work was presented at the Solomon R. Guggenheim Museum, New York, in 1965, and at the Peggy Guggenheim Collection, Venice, in 2004.