Harriet Elizabeth Prescott Spofford was born in Calais, Maine, on April 3, 1835, the eldest child of Joseph Newmarch and Sarah Jane Bridges Prescott. Her father, a lumber merchant and lawyer, suffered economic reverses and left his family in 1849 in search of better economic opportunities in Oregon. Her mother moved their five children to Newburyport, Massachusetts, where numerous Prescott relatives lived. Harriet attended Putnam Free Academy in Newburyport for four years and the Pinkerton Academy in Derry, New Hampshire, for two.

While in school Spofford's literary interest was encouraged by Thomas Wentworth Higginson, then a Unitarian minister in Newburyport. In 1856, when her father returned from the west as an invalid, Harriet became responsible for the support of her family. In 1859, her first short story, "In a Cellar," was published in the Atlantic Monthly. From the 1860s until her death in 1921 she became one of the most popular and widely published American authors. Her stories, essays, and poems appeared in Harpers, Atlantic Monthly, the Knickerbocker, Scribners, Century, Cosmopolitan, and in juvenile magazines such as the Youth's Companion. Her first novel, Sir Rohan's Ghost, was published in 1860 and her first volume of short stories, The Amber Gods, was published in 1863. Over the next 60 years she consistently published numerous other novels, collections of short stories, and poems. In Titan's Garden (1897) was her best known collection of poems. The Elder's People (1920), a series of realistic stories about New Englanders, was considered her best.

Harriet Prescott married Richard Smith Spofford, a Newburyport lawyer, in 1865. Their only child died as an infant in 1867. In 1874 the Spoffords bought Deer Island on the Merrimack River in Amesbury, Massachusetts, where they resided for the rest of their lives. She died on August 14, 1921.