Ozick received a B.A. in English in 1949 from New York University and an M.A. in 1950 from Ohio State University. Her first novel, Trust (1966), is the story of a woman's rejection of her wealthy American Jewish family and her search for her renegade father in Europe. It has echoes of Henry James (James, Henry) in its juxtaposition of American and European settings. In subsequent books, such as Bloodshed and Three Novellas (1976), Ozick struggled with the idea that the creation of art (a pagan activity) is in direct opposition to principles of Judaism, which forbids the creation of idols. The psychological aftermath of the Holocaust is another theme of her work, especially in Levitation: Five Fictions (1982) and the novels The Cannibal Galaxy (1983) and The Shawl (1989). She often drew upon traditional Jewish mysticism to expand upon her themes. One of her recurring characters is Ruth Puttermesser. In 1997 Ozick published The Puttermesser Papers, a short novel consisting of narratives and false memories of the aging Puttermesser, who in one story brings a female golem to life in order to save New York City, with disastrous results.

Ozick's later works turn away from the theme of the sacred and the profane. Her novel The Messiah of Stockholm (1987) is, in part, a meditation on the nature of writing. Heir to the Glimmering World (2004; also published as The Bear Boy) tells the story of a young woman hired as a nanny in the home of two Jewish-German academics exiled to New York City in the 1930s. Diction: A Quartet, a collection of four short stories, was published in 2008.

Many of Ozick's essays have been collected in Art & Ardor (1983), Metaphor & Memory (1989), Fame & Folly (1996), Quarrel & Quandary (2000), and The Din in the Head (2006).