Furness graduated from Harvard in 1854 and was admitted to the bar in 1859, but he soon devoted himself to the study of Shakespeare. Having accumulated a collection of illustrative material of great richness and extent, he brought out in 1871 the first volume (Romeo and Juliet) of the variorum edition, designed to represent and summarize the textual, critical, and annotative conclusions of the best authorities. Succeeding volumes appeared at regular intervals until the posthumous Cymbeline in 1913. Furness was conservative in his methods but sound in his judgments, and he combined erudition with common sense and humour. His wife, Helen Kate Furness (1837–83), compiled A Concordance to Shakespeare's Poems (1874); and his son and namesake (1865–1930) was a partner in and successor to his father's work and edited his Letters (1922).

Furness' collection is now the Horace Howard Furness Memorial Library, a section of the Department of Special Collections of the University of Pennsylvania (Pennsylvania, University of) Library.