The daughter of Don and Taylor Tartt, she was born in Greenwood, Mississippi and raised in the nearby town of Grenada. At age five, she wrote her first poem, and she was first published in a Mississippi literary review when she was 13.

Enrolling in the University of Mississippi in 1981, she pledged to the sorority Kappa Kappa Gamma. Her writing caught the attention of Willie Morris while she was a freshman. Following a recommendation from Morris, Barry Hannah, then an Ole Miss Writer-in-Residence, admitted Tartt into his graduate short story course. Following the suggestion of Morris and others, she transferred to Bennington College in 1982, meeting then-students Bret Easton Ellis and Jill Eisenstadt.

Tartt began writing her first novel, originally titled "The God of Illusions" and later published as The Secret History, during her second year at Bennington. She graduated from Bennington in 1986. After Ellis recommended her work to literary agent Amanda Urban, The Secret History was published in 1992, overwhelming the 75,000 copies in the first printing to become a bestseller. It was later translated into 24 languages.

The Secret History is set at a fictional college that closely resembles Tartt's alma mater. The plot concerns a close-knit group of six students and their professor of classics. The students embark upon a secretive plan to stage a bacchanal. The first-person narrative is flavored heavily by the differences within the group. These include: social class, privilege, intellect and sexual orientation. The narrator reflects on a variety of circumstances that lead ultimately to a murder within the group.

The fact of the murder, the location and the perpetrators are revealed in the opening pages, usurping the familiar framework and accepted conventions of the murder mystery genre. Critic A.O. Scott labeled it "a murder mystery in reverse."

The book was wrapped in a transparent acetate book jacket, a retro design by Barbara De Wilde and Chip Kidd. According to Kidd, "The following season acetate jackets sprang up in bookstores like mushrooms on a murdered tree."

The Little Friend, Tartt's second novel, was published in October 2002. It is a mystery centered on a young girl living in the American South in the late 20th century. Her implicit anxieties about the long-unexplained death of her brother and the dynamics of her extended family are a strong focus, as are the contrasting lifestyles and customs of small-town Southerners.

In 2002, it was reported that Tartt was working on a retelling of the myth of Daedalus and Icarus for the Canongate Myth Series, a series of novellas in which ancient myths are reimagined and rewritten by contemporary authors.

In September 2008, it was announced that Tartt would publish her third novel with Little, Brown and Company. The new novel, as yet untitled, is a story of loss and obsession about a young man, guilt-stricken and damaged after the death of his mother, and the growing power that a stolen piece of art exercises over him, drawing him into an underworld of theft and corruption where nothing is as it seems. Publication is scheduled for 2012.

Tartt has recorded several audiobooks: