The institution was established in 1966 by General and Mrs. L. Kemper Williams to keep their collection of Louisiana materials intact and available for research and exhibition to the public.

With the deaths of Leila and Kemper Williams, in 1966 and 1971 respectively, a foundation bearing their names was established, creating The Historic New Orleans Collection.

[10] The Merieult House on 533 Royal Street serves as the entrance to the Historic New Orleans Collection and main museum facility.

Archaeologists found indications of French barracks from the 1720s; a structure burned in the fire of 1788; a residence from the period 1790 to 1820; and debris related to the existing cottage that was built around 1830.

Built in 1915 in the Beaux Arts style, the two-story brick structure was erected to house the Second City Criminal Court and the Third District Police Station.

In 2001, THNOC acquired the largest private collection of Tennessee Williams materials anywhere in the world from collector Fred Todd.

The more rare items include notes on the filming of The Rose Tattoo, an operatic version of Summer and Smoke, a playscript for a western, a prose-poem to lover Frank Merlo, and numerous promotional materials and memorabilia from Baby Doll, including the film script with notes from director Elia Kazan and some of Williams' own financial records.

Large portions of the collection focus on the lives of Manuel "Fess" Manetta, Bunk Johnson, and Jelly Roll Morton.

The collection also features materials on brass bands, ragtime, gospel music, and William Russell's own compositions.

Major General Andrew Jackson, military commander during these events, is well represented, and the collection also includes various important U.S. Army and militia documents, as well as materials concerning the participation of the southern Indian tribes and manuscripts from the British perspective.

The collection includes an assortment of prints, photographs, postcards, letterheads, maps, sheet music and other objects.

The J. Hanno Deiler Papers contain hand-written and typescript drafts of the historian's major books, articles, and speeches, as well as a number of genealogies of Louisiana-German families.