Patchett was born in Los Angeles, California. She moved to Nashville, Tennessee when she was six, where she continues to live.Her mother is the novelist Jeanne Ray.

Patchett attended high school at St. Bernard Academy, a private, non-parochial Catholic school for girls run by the Sisters of Mercy. . Following graduation, she attended Sarah Lawrence College and took fiction writing classes with Allan Gurganus, Russell Banks, and Grace Paley. She later attended the Iowa Writers' Workshop at the University of Iowa and the Fine Arts Work Center in Provincetown, Massachusetts, where she met longtime friend Elizabeth McCracken. It was also there that she wrote her first novel, The Patron Saint of Liars.

Patchett's first published work was in The Paris Review. She sold her story to the journal and had it published before she graduated from Sarah Lawrence College.

For nine years, Patchett worked at Seventeen magazine. She mostly wrote non-fiction, and the magazine would publish only one of every five articles she wrote. She said that the magazine was cruel and eventually she stopped taking criticism personally. She ended her relationship with the magazine after getting into a fight with an editor and exclaiming, "I’ll never darken your door again!"

In 1992, Patchett published The Patron Saint of Liars. The novel was made into a movie of the same title in 1998.

Her second novel Taft won the Janet Heidinger Kafka Prize in fiction in 1994. Her third novel, The Magician’s Assistant, was released in 1997. In 2001, her fourth novel Bel Canto became her breakthrough, winning many awards, including the PEN/Faulkner Award, and becoming a National Book Critics Circle Award Finalist.

She was friends with fellow writer Lucy Grealy and has written a memoir about their relationship, Truth and Beauty: A Friendship. Patchett's latest novel, Run, was released in October 2007. What now?, published in April 2008, is an essay based on a commencement speech she delivered at her alma mater in 2006.

Patchett has written for numerous publications, including The New York Times Magazine, The Washington Post, O, The Oprah Magazine, ELLE, GQ, Gourmet, and Vogue. She is the editor of the 2006 volume of the anthology series The Best American Short Stories.

Novels

• The Patron Saint of Liars (1992)
• Taft (1994)
• The Magician's Assistant (1997)
• Bel Canto (2001)
• Run (2007)

Nonfiction

• A Friendship (2004)
• What now? (2008)