Sena Jeter Naslund was born in Birmingham, Alabama; her mother taught music and her father, who died when she was 15, was a doctor; she has two older brothers.  In high school she played cello with the Alabama Pops Orchestra. She won a music scholarship to the University of Alabama but turned it down in favor of studying writing at Birmingham-Southern College, while she was there she attended the Breadloaf Writers' Conference - a two week series of lectures, workshops and classes (since 1926, the conference has been held annually at the Breadloaf Inn, Middlebury, Vermont and claims to be the oldest writers' conference in the USA).

After graduating from Birmingham-Southern, she was accepted at the Iowa Writers' Workshop at the University of Iowa where she received her MA and PhD degrees in creative writing.  In 1971 she was hired as a Visiting Professor in the MFA program at the University of Montana. The following year, she accepted a teaching position at the University of Louisville in Kentucky, where she directed the creative writing program and was awarded the university's first Distinguished Teaching Professor honor.

She is currently Writer in Residence at the University of Louisville, program director of the Spalding University brief-residency MFA in Writing, and Kentucky Poet Laureate.  She is also the editor of The Louisville Review and the Fleur-de-Lis Press (both founded by her in 1976).

She is the author of the novels Sherlock in Love (1993), The Animal Way to Love (1993), Ahab's Wife (1999), Four Spirits (2003), Abundance (2006); and two collections of stories: Ice Skating at the North Pole (1989) and The Disobedience of Water (1997).

Her fiction has been published in many journals including The Paris Review, The Georgia Review, The Iowa Review, The Michigan Quarterly Review (where she won the Lawrence Prize in fiction), The Indiana Review, and The Alaska Quarterly Review. She has received grants from the National Endowment for the Arts, the Kentucky Foundation for Women, and the Kentucky Arts Council, and has won the Harper Lee Award and the Southeastern Library Association Fiction Award.

She lives in Louisville, Kentucky with her husband John C. Morrison, an atomic physicist, and their daughter, Flora.