Born in Memphis, Tennessee. She attended Miss Hutchison's School and three different universities, without obtaining a degree. According to her obituary in the New York Times, Fitzhugh graduated from Barnard College in 1950. She lived most of her adult life in New York City and had houses in both Long Island and Bridgewater, Connecticut.
She was married briefly to Ed Thompson, whom she dated in high school. After high school, she primarily dated women.
Fitzhugh was the illustrator of the 1961 children's book Suzuki Beane, a parody of Eloise; while Eloise lived in the Plaza, Suzuki was the daughter of beatnik parents and slept on a mattress on the floor of a Bleecker Street pad in Greenwich Village. Fitzhugh worked closely with author Sandra Scoppettone to produce Suzuki Beane, which incorporated typewriter font and line drawings in an original way. Although a parody of both Eloise and beatnik conceit, the book sprang to life as a genuine work of literature. Today, it is a much sought-after book on used-book websites.
Fitzhugh's best-known book was Harriet the Spy, published in 1964 to some controversy since so many characters were far from admirable. It has since become a classic. As her New York Times' obituary, published November 19, 1974, states: "The book helped introduce a new realism to children's fiction and has been widely imitated". Harriet is the daughter of affluent New Yorkers who leave her in the care of her nanny, Ole Golly, in their Manhattan townhouse. Hardly the feminine girl heroine typical of the early 1960s, Harriet is a writer who notes everything about everybody in her world in a notebook which ultimately falls into the wrong hands. Ole Golly gives Harriet the unlikely but practical advice that: "Sometimes you have to lie. But to yourself you must always tell the truth". By and large, Harriet the Spy was well-received -- it was awarded a New York Times Outstanding Book Award in 1964 -- and has sold 4 million copies since publication. Two characters from the book, Beth Ellen and Sport, were featured in two of Fitzhugh's later books, The Long Secret and Sport. The Long Secret deals fairly honestly with female puberty; the main characters are pre-teen girls who discuss how their changing bodies feel.
Fitzhugh illustrated many of her books and had works exhibited in Banfer Gallery, New York, in 1963, among many other galleries.
She died in 1974 of a brain aneurysm. Her obituary was published in the New York Times.