The son of David and Elizabeth Bender, he was born in Boston on September 6, 1805, into a home with ethics for honesty and emphasis on good education. Horatio sparked an interest in artistic and mechanical hobbies, showing his native skills and talents at a young age. Particularly attracted to chalk, around the age of 12 he made a chalk statue of William Penn, known as his earliest work of record. Horatio also experimented with clay, from which he learned from Solomon Willard. He also learned how to carve with marble under instruction from Alpheus Cary. Horatio seemed to have a natural talent for art, yet his father wasn’t fond of the idea of this as a career for Horatio.

In 1814 Horatio Greenough enrolled at Phillips Academy, Andover, and in 1821 he entered Harvard University. There he found a passion in works of antiquity and devoted much of his time to reading literature and works of art. With a plan to study abroad, he learned Italian and French, but also still studied anatomy and kept modeling sculptures. While attending Harvard he came across his first crucial influence. Washington Allston was more than a mentor, but a close friend who enlightened and inspired Horatio. He even molded a bust of Washington. Before graduating from Harvard, he sailed to Rome to study art where he met the painter Robert W. Weir, while living on Via Gregoriana. These two became close friends and studied together the Renaissance and works of antiquity. Favorites of theirs were the Laocoon group of the Vatican structure galleries and the Apollo Belvedere. During Horatio’s time spent in Rome he created many busts, as well as a full-size statue of the Dead Abel, and a portrait of himself. He returned to Boston in May 1827 with Weir, after recovering from an attack of malaria. He then modeled more busts such as Josiah Quincy, president of Harvard, Samuel Appleton and John Jacob Astor. Horatio’s recognition was still not seen, so in an attempt to establish a successful reputation he sought out to make a portrait of President John Quincy Adams. His plan worked as he really displayed a style of naturalism in this piece as he did in many other works.

His sculptures reflected truth and reality, but also ancient classical aesthetic ideals which he learned from Washington Allston. Many of Horatio’s captured works were done in Florence, Italy, where he spent most of his professional life. His sculpture The Rescue (1837 – 1850) and his over life-size George Washington (1840) both derived from United States government commissions. Some of his other most famous and important sculptures include: James Fenimore Cooper, 1831, Castor and Pollux, 1847, Marquis de Lafayette, 1831-32. Along with sculpture masterpieces he created, there are numerous drawings he also created which are displayed at the Middlebury College Museum of Art's exhibition.

Greenough’s probably most enduring achievements are his essays on art. Here Greenough repeatedly criticized contemporary American architecture for its imitation of European historical building styles, wrote enthusiastically about the beauty of animal bodies, of machine constructions, and of ship design, and argued that as to architecture, formal solutions were inherent in the functions of the building; in this he anticipated the later functionalist thinking. The origin of the phrase form follows function is often, but wrongly, ascribed to Greenough, although the theory of inherent forms, of which the phrase is a fitting summary, informs all of Greenough's writing on art, design, and architecture. The phrase itself was coined by the architect Louis Sullivan, Greenough's much younger compatriot, in 1896, some fifty years after Greenough's death. Greenough, just as Sullivan himself, was influenced by the transcendentalist thinking and the unitarian religion of Ralph Waldo Emerson who wrote, e.g., in his essay on "Nature" (1836), that "Nature who made the mason, made the house." Greenough's writings were for a long time largely forgotten, and were rediscovered only in the 1930s; in 1947 a selection of his essays was published under the title Form and Function: Remarks on Art by Horatio Greenough.

Although Greenough was generally healthy, in December 1852 he contracted a severe fever. On December 18, after two weeks of this high fever he died at the age of 47 in Somerville, near Boston. Greenough worked hard to gain the recognition, yet still little is focused upon him. As one of America's first sculptors to gain international fame, he is historically important.