Built in 1918 to replace the older Orpheum, the new Orpheum Theatre opened with great pomp and circumstance on February 5, 1921, with a matinee performance in the afternoon.  However, according to the coverage of the New Orleans Item, “The real opening of the magnificent theatre did not take place until the evening, when an audience socially brilliant and thoroughly representative of the city’s life assembled to get a first glimpse at one of the finest theaters in America…like a gala night at the opera.”  However, the wealthy and lavish were not the Orpheum’s only patrons, nor was their presence at its opening “thoroughly representative of the city’s life,” as the Item proclaimed.
The Orpheum was segregated. The first balcony was reserved for white customers, and its stairs rose from the orchestra foyer. The second balcony was sanctioned "colored only" and its stairs rose from the exterior alleys.  It was a three-story building with luxurious appointments including marble mosaic floors in the lobbies. The building had at least twenty two dressing rooms spread throughout all three stories. 
The Keith-Orpheum Circuit provided the Orpheum with vaudeville acts, which were considered “big time“ as compared to the Loew Circuit and aimed at a “classy audience,” the kind that went to Broadway plays. 
A film projector was placed in the original plans for the building. While the Orpheum was primarily intended as a stage theatre, it is significant that a motion picture projector would share the space at this point in time. The Orpheum in New Orleans became the recipient of the films, and by 1931, they had surpassed vaudeville as the main attraction of the theater.  The onset of the Great Depression fueled both musicians and stagehand strikes enough to force the Orpheum to drop vaudeville altogether.  By the end of the 1930s, the Orpheum showed only full-length feature films and also became the home of RKO pictures.
In 1981, the Orpheum Theatre underwent an extensive renovation keeping most of its historical form and details. Since then, the New Orleans Symphony (later, renamed the Louisiana Philharmonic in 1991) played there until 2005 when Hurricane Katrina hit.  The theatre sat empty and filled with water until 2010. The theater reopened in 2015 after extensive restorations.