Harriet Prescott moved from her native Maine to Newburyport, Massachusetts, in 1849 and attended the Pinkerton Academy in Derry, New Hampshire, in 1853–55. In part to aid the family's precarious finances and with the encouragement of social reformer and author Thomas W.S. Higginson (Higginson, Thomas Wentworth), she turned to writing. Several of her stories were published in Boston newspapers, and her tale “In a Cellar” appeared in the Atlantic Monthly in 1859. In 1860 her first novel appeared anonymously as Sir Rohan's Ghost. She published The Amber Gods (1863), a collection of stories, and Azarian: An Episode (1864), a novel, before marrying Richard S. Spofford in 1865.

She continued to write prolifically, and her stories, essays, travel sketches, and poems appeared in the Atlantic, Scribner's, Century, Harper's Bazaar, and other leading magazines. Her published volumes include New-England Legends (1871), Art Decoration Applied to Furniture (1878), The Servant Girl Question (1881), Ballads About Authors (1887), A Scarlet Poppy, and Other Stories (1894), Old Madame, and Other Tragedies (1900), Old Washington (1906), The Fairy Changeling (1910), A Little Book of Friends (1916), and The Elder's People (1920). Her home was frequented by literary personages, especially the many women writers who were her friends.