Harriet Hosmer was born at Watertown, Massachusetts. She showed an early aptitude for modeling, and studied anatomy with her father, a physician, and afterwards at the St Louis Medical College. She then studied in Boston until 1852, when, with her friend Charlotte Cushman, she went to Rome, where from 1853 to 1860 she was the pupil of the English sculptor John Gibson.

While living in Rome, she was associated with Nathaniel Hawthorne, Thorvaldsen, Thackeray, George Eliot and George Sand; and she was frequently the guest of the Brownings at Casa Guidi, in Florence. Later she also resided in Chicago and Terre Haute, Indiana.

Novelist Henry James unflatteringly referred to the group of women artists in Rome of which she was a part as "The White Marmorean Flock," borrowing a term from Nathaniel Hawthorne in The Marble Faun. These artists included lesbians Anne Whitney, Emma Stebbins, Edmonia Lewis and non-lesbians Louisa Lander, Margaret Foley, Florence Freeman, and Vinnie Ream.

Hosmer died at Watertown, Massachusetts, on February 21, 1908.