Her memoir The Liars' Club, published in 1995, was a New York Times bestseller for over a year, and was named one of the year's best books. It delves vividly and often humorously into her deeply troubled childhood, most of which was spent in a gritty industrial section of Southeast Texas in the 1960s. She was encouraged to write her personal history by her friend Tobias Wolff, but has said she only took up the project when her marriage fell apart.

She followed the book with another memoir, Cherry (2000), about her late adolescence and early womanhood.

A third memoir, Lit: A Memoir, which she says details "my journey from blackbelt sinner and lifelong agnostic to unlikely Catholic," came out in November 2009. She writes about her time as an alcoholic and the salvation she found in her conversion to Catholicism.

Karr thinks of herself first and foremost as a poet. She was a Guggenheim Fellow in poetry in 2005 and has won Pushcart prizes for both her poetry and her essays. Karr has published four volumes of poetry: Abacus (Wesleyan University Press, CT, 1987, in its New Poets series), The Devil's Tour (New Directions NY, 1993, an original TPB), Viper Rum (New Directions NY, 1998, an original TPB), and her new volume Sinners Welcome (HarperCollins, NY 2006). Her poems have appeared in major literary magazines such as Poetry, The New Yorker, and The Atlantic Monthly.

She is a controversial figure in the American poetry "establishment," thanks to her Pushcart-award winning essay, "Against Decoration," which was originally published in the quarterly review Parnassus (1991) and later reprinted in Viper Rum. In this essay Karr took a stand in favor of content over poetic style. She argued emotions need to be directly expressed, and clarity should be a watch-word: characters are too obscure, the presented physical world is often "foggy" (that is imprecise), references are "showy" (both non-germane and overused), metaphors over-shadow expected meaning, and techniques of language (polysyllables, archaic words, intricate syntax, "yards of adjectives") only "slow a reader"'s understanding. Karr directly criticized well-known, well-connected, and award-winning poets such as James Merrill, Amy Clampitt, Vijay Seshadri, and Rosanna Warren (daughter of Pulitzer Prize winner Robert Penn Warren). Karr favors controlled elegance to create transcendent poetic meaning out of not-quite-ordinary moments, presenting James Merrill's "Charles on Fire" as a successful example.

Karr's essay is meant to provide the technical detail to Randall Jarrell's argument. As a result of this essay Karr earned a reputation for being both courageous and combative, a matured version of the BB-gun toting little hellion limned in The Liars' Club.

Another essay, "Facing Altars: Poetry and Prayer", was originally published in Poetry (2005). Karr tells of moving from agnostic alcoholic to baptized Catholic of the decidedly "cafeteria" kind, yet one who prays twice daily with loud fervor from her "foxhole". In this essay Karr argues that poetry and prayer arise from the same sources within us.

Karr was born January 16, 1955, in Groves, a small town in South East Texas located in the Port Arthur region, known for its oil refineries and chemical plants, to J. P. and Charlie Marie (Moore) Karr. In her memoirs, Karr calls the town "Leechfield." Karr's father worked in an oil refinery while her mother was an amateur artist and business owner. Karr's sister, two years her elder, is a key figure in her memoirs. Karr developed an early interest in literature; she told a Publishers Weekly interviewer that, at the age of eleven, she wrote in a notebook that her ambition was “to write poetry and autobiography.” Upon graduation from Port Neches-Groves High School, she traveled with a group of friends to Los Angeles, where she immersed herself in the lifestyle of the California hippie and surfer counter-cultures. Later that year, she enrolled in Macalester College in Saint Paul, Minnesota, but left school after two years to travel. Her political involvement in the anti-apartheid movement led her to meet African American poet Etheridge Knight who became an important influence on the development of her poetry. Karr eventually entered graduate school to study creative writing, and earned an M.F.A. from Goddard College in 1979. Among her mentors at Goddard was Tobias Wolff, whose memoir This Boy's Life served as a major influence on Karr's own writing. She also studied with noted poets Robert Bly and Robert Hass. Her first publication was a poem that appeared in Mother Jones magazine. Karr moved to Boston in 1980, where she held various jobs in the computer and telecommunications industries while continuing to write and publish poetry. In 1983 she married poet Michael Milburn, with whom she had a son, but the couple divorced in 1991. In the 90s, Karr dated David Foster Wallace. Karr has worked as an assistant professor at several colleges and universities, including Tufts University, Emerson College, Harvard University, and Sarah Lawrence College. She currently teaches in the department of English at Syracuse University in Syracuse, New York. She has been featured on NPR radio and CSPAN's Book TV.