Grace Hartigan was born on March 28, 1922, in Newark, New Jersey. In 1942 she enrolled at the Newark College of Engineering and supported her family by practicing mechanical drafting in an aircraft factory, while making watercolors on the side. Introduced to the work of Henri Matisse from a book loaned by a fellow student, she developed a lifelong interest in modern art. She moved to New York after World War II and began to engage in the world of Abstract Expressionism, befriending Milton Avery, Adolph Gottlieb, and Mark Rothko, in particular. But it was not until January 1948, after seeing a Jackson Pollock exhibition at the Betty Parsons Gallery, that Hartigan began to form her own, inimitable Abstract Expressionist sensibility. Hartigan spent a week with Pollock and his wife, artist Lee Krasner, at their home in the Hamptons, and Pollock encouraged her to look at the work of Willem de Kooning. Hartigan followed De Kooning's lead by studying the Old Masters and rejecting theoretical divisions between representation and abstraction.

Inspired by Pollock's allover gestural style and all-encompassing scale and De Kooning's devotion to art history, Hartigan began inserting recognizable imagery into her abstractions, which often consisted of fairly dense networks of geometric shapes. This shift from her initial seemingly pure abstractions earned her a solo debut at New York's Tibor de Nagy Gallery in 1951. In 1952 she spent a year making studies based on Old Master paintings, resulting in a temporary rift from many of her Abstract Expressionist friends, such as Joan Mitchell, and the loss of support from critic Clement Greenberg, who had featured her in New Talent, cocurated with art historian Meyer Schapiro for the Kootz Gallery, New York, in 1950. But Hartigan's paintings were included in 12 Americans at the Museum of Modern Art (MoMA), New York (1956), and in The New American Painting, which was coorganized by MoMA and the United States Information Agency and traveled to eight European cities from 1958 to 1959. As one of few women painters to receive that level of exposure, Hartigan garnered significant press coverage and was featured in Life magazine in 1957 and Newsweek in 1959.

Toward the end of the 1950s, Hartigan experimented with a freer gestural technique. Though she fiercely opposed Pop art, which emerged at this time, some Pop elements are present in her landmark painting Marilyn (1962), a pastiche of the film star Marilyn Monroe, which scatters facial features such as full lips and sparkling teeth across the canvas. Hartigan continued to refer to Old Masters such as El Greco and Jean-Baptiste Greuze and to experiment with balancing figuration and abstraction, but her later work, from the 1980s through the 2000s, tended toward the representational. Her second marriage necessitated a move from New York to Baltimore in 1960, and from 1965 until her death in 2008, she served as a teacher at and director of the prestigious Hoffberger Graduate School of Painting, Maryland Institute College of Art, Baltimore.

Hartigan's work was included in the seminal Ninth Street Show, New York (1951), as well as other major group exhibitions at the Jewish Museum, New York (1957); Documenta, Kassel, West Germany (1959); Guggenheim Museum (1961); Whitney Museum of American Art, New York (1989, 1999); Museum of Contemporary Art, Los Angeles (1992, 1999). Aside from regular solo gallery shows at Tibor de Nagy (1951–59) and then Martha Jackson Gallery (1962–70), Hartigan's work was featured in solo exhibitions at Baltimore Museum of Art (1980); Skidmore College, Saratoga Springs, New York (1993); and Neuberger Museum of Art, Purchase, New York (2001). Hartigan died on November 15, 2008, in Baltimore.

Grace Hartigan was included in the 2016 ground breaking exhibition at the Denver Art Museum entitled "Women of Abstract Expressionism". The major publication published for this traveling exhibition has been the catalyst for much greater attention on these significant artists.

In 2023 her work was included in the exhibition Action, Gesture, Paint: Women Artists and Global Abstraction 1940-1970 at the Whitechapel Gallery in London.