Hustvedt was born in Northfield, Minnesota. Her father Lloyd Hustvedt was a professor of Scandinavian literature, and her mother Ester Vegan emigrated from Norway at the age of thirty. She holds a B.A. in history from St. Olaf College and a Ph.D. in English from Columbia University; her thesis on Charles Dickens was entitled Figures of Dust: A Reading of Our Mutual Friend.

Hustvedt has mainly made her name as a novelist, but she has also produced a book of poetry, and has had short stories and essays on various subjects published in (among others) The Art of the Essay, 1999, The Best American Short Stories 1990 and 1991, The Paris Review, Yale Review, and Modern Painters.

Like her husband Paul Auster, Hustvedt employs a use of repetitive themes or symbols throughout her work. Most notably the use of certain types of voyeurism, often linking objects of the dead to characters who are relative strangers to the deceased characters (most notable in various facits in her novels The Blindfold and The Enchantment of Lily Dahl) and the exploration of identity. She has also written essays on art history and theory (see "Essay collections") and painting and painters often appear in her fiction, most notably, perhaps, in her novel, What I Loved.

She lives in Brooklyn, New York, with her husband, writer Paul Auster, and their daughter, singer and actress Sophie Auster.