Barbara Grizzuti was born in Queens, New York City, on September 14, 1934. Her parents were first-generation Americans; her grandparents were immigrants from Calabria in Southern Italy. She later described her childhood as deeply troubled. Her mother, who apparently suffered from mental illness, was emotionally distant and insisted on describing herself as "Barbara's relative", not her mother. Near the end of her life Harrison also claimed that her father had sexually abused her. The turmoil of her childhood would have a strong influence on her writing.

In 1960 Barbara Grizzuti married W. Dale Harrison, an aid worker for Cooperative for Assistance and Relief Everywhere (CARE). The couple spent the eight years of their marriage living in Tripoli, Mumbai, Hyderabad, India, and Chichicastenango. The Harrisons had a son, Joshua, and a daughter, Anna. They divorced in 1968, and Barbara returned to New York with the children.

By now Harrison had become involved with the women's movement, and she began writing on feminist themes for various publications. Her first book, Unlearning the Lie: Sexism in School, was published in 1969. Harrison was one of the first contributors to Ms. magazine.

Harrison became nationally known in 1978 when she published Visions of Glory: A History and a Memory of Jehovah's Witnesses, which combined childhood memoirs with a history of the Jehovah's Witness movement. Although Harrison expressed admiration for individual Witnesses and wrote sympathetically of their persecution, she portrayed the faith itself as harsh and tyrannical, racist and sexist.

Harrison published two collections of her essays and interviews: Off Center (1980) and The Astonishing World (1992). Her 1992 Harper's essay "P.C. on the Grill", which lampooned the "philosophy" of popular TV chef The Frugal Gourmet, was included in the 1993 edition of Best American Essays.

In 1984 Harrison published a novel, Foreign Bodies. She won an O. Henry Award for short fiction in 1989.

Harrison also wrote numerous travel articles covering destinations all over the world. She published two books about her travels in Italy, Italian Days (1989) and The Islands of Italy: Sicily, Sardinia, and the Aeolian Islands (1991).

In 1994 Harrison, who had been a heavy smoker for most of her adult life, was diagnosed with chronic obstructive pulmonary disease. During her illness she completed her last book, An Accidental Autobiography. As the title implied, the book was less a straightforward memoir than a stream-of-consciousness collection of memories and reflections, loosely organised by theme.

Harrison wrote little afterwards as her illness progressed. She died on April 24, 2002 in a hospice in Manhattan.