She was born as Harriette Louisa Simpson in Bronston,Wayne County, Kentucky, and grew up in neighboring Pulaski County. Her father, a former teacher, worked in factories and oil fields, and her mother, also a former teacher, raised her to be a teacher, too. She taught for a number of years in a one-room school house in Kentucky. Harriet was one of six siblings - 5 girls and 1 boy in a family that could trace its roots back to the Revolutionary War era..

Arnow wanted to write and also to develop her knowledge of the land and geology. She attended Berea College for two years before transferring to the University of Louisville. She worked for two years as a teacher in rural Pulaski County, then one of the wilder parts of a region on the outskirts of Appalachia, before moving to Cincinnati, where she published her first works in 1935, two short stories ... "A Mess of Pork" and "Marigolds and Mules" ... under the pseudonym H.L. Simpson along with a photo of her brother-in-law to disguise her gender from the editors of Esquire.

In 1936 she published her first novel, Mountain Path, basing it on her experiences as a teacher. Under the instructions of her publisher, Arnow added sensational "Appalachian" stereotypical elements (moonshining, feuds) to her original work, a much more sedate series of sketches.

From 1934-1939 she lived in Cincinnati and worked for the Federal Writer's Project of the WPA where she met her future husband, Harold B. Arnow, the son of Jewish immigrants, in 1939. They lived briefly in Pulaski County, Harriette again working as a teacher, before settling in a public housing complex in Detroit, Michigan in 1944. Her 1949 novel, Hunter's Horn, was a best seller and received considerable critical acclaim, finishing close to William Faulkner's A Fable in that year's voting for the Pulitzer Prize.

In 1950 they moved to Ann Arbor, Michigan. She published her most famous work The Dollmaker in 1954. This novel about a poor Kentucky family forced by economic necessity to move to Detroit reflected her own life, but also reflects the experiences of many Appalachians who migrated from their homes for the promise of better lives in the industrialized North. Told through the eyes of Gertie Nevels, a woman torn from her beloved woods and farmland to move with her children to join her husband living in WWII factory workers' housing in Detroit,it is often studied as a work of feminist fiction. Arnow herself disputed this characterization however, preferring to see it as an individual woman's struggle to survive in a harsh and changing world

Later works included the historical studies Seedtime on the Cumberland and Flowering of the Cumberland. Her last books were the novels The Weedkiller's Daughter, 1970, The Kentucky Trace, 1974, and the memoir Old Burnside, 1977.

She died in 1986, aged 77, at her farm in Washtenaw County, Michigan. Michigan State University Press brought out her previously unpublished second novel, Between the Flowers, in 1999, and The Collected Short Stories of Harriette Simpson Arnow in 2005.