Spofford was born in Gilmanton, New Hampshire. Ill health prevented him from attending Amherst College. He instead, at age 19, moved to Cincinnati, Ohio, where he became a bookseller, publisher, and newspaper man. In 1851, in response to the Fugitive Slave Law, he published the pamphlet The Higher Law, Tried by Reason and Authority which argued that "Injustice is the only treason; no law can legalize it, no constitution can sanction it." Readers included Ralph Waldo Emerson, who shared Spofford's antislavery principles. In 1859 Spofford became associate editor of the Cincinnati Commercial. He was also active in Republican party politics and was a delegate to the nominating convention of John Charles Frémont in 1856.
While in Washington D.C. in 1861, shortly after reporting on the Battle of Bull Run for The Cincinnati Commercial, Spofford accepted the position of Chief Assistant Librarian of Congress. Once Spofford learned of the retirement of Librarian of CongressJohn G. Stephenson, Spofford gather enough political endorsements for the job which later led President Abraham Lincoln to promote Spofford to post of Librarian of Congress in 1864.
The Library of Congress began as a comprehensive collection under the donation of Thomas Jefferson in 1814. However, the Library of Congress shifted to a very domestic collection management program until the end of the Civil War. Spofford adhered to the Jeffersonian belief that a “democratic form of government depended on a comprehensive base of knowledge and information.” That has been the legacy of Spofford, and one that each Librarian of Congress since has built upon.
Spofford is generally credited with overseeing the expansion of the Library from a Congressional resource into a national institution. During Spofford's tenure, the Library expanded from over 60,000 items to more than one million. His hopes were to follow the great library models of Europe. A model in which "the library would be a comprehensive collection of the literature of the nation.
Beginning in the 1830’s, the Library of Congress began to receive foreign governmental documents and publications. During the late 1860’s, Spofford convinced Congress to allow the Library of Congress to become the repository for international documents. Spofford often received congressional approval by reminding them "there is almost no work, within the vast range of literature and science, which may not at some time prove useful to the legislature of a great nation. Furthermore, the entire Smithsonian Library transferred their entire collection to the Library of Congress.
Spofford's vision was to turn the Library of Congress into an "American national library". He felt that Americans deserved a national collection because America was a "Republic, which rests upon popular intelligence." One of Spofford's greatest feats was the copyright law of 1870. It further centralized the collection of the Library of Congress. It stipulated that two copies of every "book pamphlet, map, print, photograph, and piece of music registered for copyright be deposited in the Library, a requirement that certainly would have met with Jefferson's approval. Spofford knew that this massive influx of materials would also force Congress to appropriate funds for a new building, which they finally agreed to in 1886. This building became a national monument immediately, and is now known as the Thomas Jefferson Building.
Spofford stepped aside in favor of a younger administrator, John Russell Young, and returned to his old post of Chief Assistant Librarian, where he remained until his death.