Barrett was born in Boston, Massachusetts. She earned a B.A. in biology from Union College and briefly attended a Ph.D. program in zoology.

Barrett began writing fiction seriously in her thirties, but was relatively unknown until the publication of Ship Fever. The collection of novella and short stories won the National Book Award in 1996. Barrett received a MacArthur Fellowship in 2001. Her short story collection Servants of the Map was a finalist for the 2003 Pulitzer Prize for Fiction.

Barrett is particularly well known as a writer of historical fiction. Her work reflects her lifelong interest in science, and women in science. Many of her characters are scientists, often 19th-century biologists.

Barrett teaches at Williams College in Massachusetts and in the Warren Wilson College MFA Program for Writers in North Carolina. She was a fellow at the Center for Scholars and Writers at the New York Public Library. She lives in North Adams, Massachusetts.

As in the work of William Faulkner, some of her characters have appeared in more than one story or novel. In an appendix to her recent novel, The Air We Breathe (2007), Barrett supplied a family tree, making clear the characters' relationships that began in Ship Fever. Although each novel and story is self-contained, the reader comprehends an added dimension when familiar with the characters' previous histories.