The Maginnis Cotton Mill was constructed in 1882 by Arthur A. Maginnis, a wealthy son of Irish immigrants who reigned as King of Carnival in 1880. When A. A. Maginnis purchased the property in 1881, the city square bounded by Annunciation, Constance, John Churchill Chase and Poeyfarre Streets was occupied by a lumberyard, modest working-class houses and a plantation house. These buildings were torn down to make room for the mill which became the largest cotton mill in the gulf south. It produced everything from burlap sacks and sail cloths to fine muslin and ladies' hosiery, churning out 21,000,000 yards of cotton annually.

At its peak, the mill employed more than 1,000 men, women and children, most of them Irish immigrants. The Maginnis family sold the business in 1914 after being indicted for tax fraud. The mill continued to produce cotton products, but by World War II, parts of the building were leased to various businesses which produced ties and sportswear. The building officially closed in the mid-1980s.

In December, 1996, the Cotton Mill Limited Partnership sponsored archaeological excavations on the grounds which led to the discovery of a mill-era privy (or outhouse), 19th century tenement buildings and the well-preserved floor and foundation of the Duplesses Plantation house which dates back to 1765. Pieces of this archaeological excavation and full history of the land where the Cotton Mill sits can be found in an exhibit in the Cotton Mill lobby.