Born in Boston, Massachusetts, Homer was apprenticed to a Boston commercial lithographer at the age of 19. By 1857 his freelance illustration career was underway and he contributed to magazines such as Ballou's Pictorial and Harper's Weekly.

His works, mostly engravings, are characterized by clean outlines, simplified forms, dramatic contrast of light and dark, and lively figure groupings - qualities that remained important throughout his career.

In 1859 he opened a studio in New York City, and began his painting career.

Harper's sent Homer to the front lines of the American Civil War (1861 - 1865), where he sketched battle scenes and mundane camp life. Although the drawings did not get much attention at the time, they influenced much of his later work.

Back at his studio after the war, Homer set to work on real war-related paintings, among them Sharpshooter on Picket Duty, and Prisoners from the Front which is noted for its objectivity and realism.

After exhibiting at the National Academy of Design, Homer traveled to Paris, France in 1867 where he remained for a year. He practiced painting landscapes while continuing to work for Harper's. Though his interest in depicting natural light parellels the impressionists interest in natural light, the group did not directly affect his work.

Throughout the 1870s he portrayed mostly rural or idyllic scenes of farm life, children playing, and resorts. Homer gained acclaim as a painter in the late 1870s and early 1880s. His 1872 composition, Snap-the-Whip, showed at the 1876 Centennial Exposition in Philadelphia, Pennsylvania. Homer was a member of the The Tile Club, a group of artists and writers who met frequently to exchange ideas and organize outings for painting. Homer's nickname in The Tile Club was The Obtuse Bard. Other well known Tilers were painters William Merritt Chase, Arthur Quartley, and Augustus Saint Gaudens.

In 1873 he started painting with watercolours, and the medium became as important to him as oil paint. His watercolor paintings show a fresh, spontaneous, loose, yet natural style. Thereafter, Homer seldom went anywhere without paper, brushes and water paints. Homer once remarked,

"You will see, in the future, I will live by my watercolors". In 1875 he quit working as a commercial illustrator, and concentrated on painting.

He travelled widely, spending two years (1881 - 1882) in the English coastal village of Cullercoats, Northumberland, where he rekindled his boyhood interest in the sea, and painted the local fishermen and their families.

Back in the U.S., he moved to Prout's Neck, Maine (near Scarborough) and painted the seascapes for which he is perhaps best known. Notable among these dramatic struggle-with-nature images are Banks Fisherman, Eight Bells, Gulf Stream, Rum Cay, Mending the Nets, and Searchlight, Harbor Entrance, Santiago de Cuba.

To find inspiration for his seascapes, Homer often ventured during the winter to locations such as Florida and the Caribbean.

Homer died at the age of 74 in his Prout's Neck studio and was interred in the Mount Auburn Cemetery in Cambridge, Massachusetts. His painting, Shoot the Rapids, remained unfinished.