One of the oldest theaters in the United States as designed by Snell and Gregerson, it was built in 1852 and was originally known as the Boston Music Hall.

It was converted in 1900 to a design by Little and Browne, for use as a vaudeville theater and operated under a number of different names, including the Music Hall and the Empire Theatre.

The original organ, built in Germany, was removed in that renovation and rehoused in the purpose-built Methuen Memorial Music Hall by 1909.

African-American business owner and activist Arthur Scott of Boston's Dorchester neighborhood obtained a 10-year lease on the venue and became its general manager.

It was the site of several significant American premiers including: Berlioz Les Troyens (1972), Verdi Don Carlos in the original five-act French version (1973), Prokofiev War and Peace (1975), Berlioz Benvenuto Cellini (1975), Sessions Montezuma (1976), Glinka Ruslan and Ludmila (1977), and the first major American production of Verdi Stiffelio (1978).

During that period, America's most popular diva, Beverly Sills, made annual appearances, performing: Norma, La Traviata, Daughter of the Regiment, Barber of Seville, I Capuletti ed i Montecchi, Rigoletto, and Don Pasquale.

The contract to operate the Orpheum was acquired by Don Law, a Boston concert promoter, from the Live Nation entertainment company, in 2009.