There is evidence of Catholic presence and activity in Natchez from 1700 onward. In 1722, a French Catholic parish was established. The Spaniards conquered the Natchez area in 1779. A Spanish Catholic Church, San Salvador was erected in 1788. In 1793 Natchez became part of the Diocese of Louisiana. Natchez Catholics maintained their own community without a resident priest from 1798 – 1839.  

The Diocese of Natchez, with responsibility for the entire state of Mississippi, was established in 1837. Bishop John J. Chanche arrived as first bishop in 1841.  

Not long after his arrival, he began preparation to build his Cathedral. The cornerstone was laid on February 24, 1842 . It was dedicated on December 25, 1843.  The church took 40 years to be completed. It was consecrated on September 19, 1886 and remained the Cathedral of the Diocese until 1977.  

Twelve of its beautiful stained glass windows, by Tyroler Glassmalerie, Innsbruch ( Germany ), were installed between 1884 – 1893, and four, by Emil Frei, St Louis, Missouri, were installed in 1961.  

The three marble altars, communion rail, Episcopal chair, and screens are in Carrara marble, fashioned in Italy in Gothic style for St. Mary were installed in 1930. The new altar of celebration and pulpit were installed in 1991.  

On September 8, 1998, St Mary was designated as a Minor Basilica and was formally dedicated as a Minor Basilica on September 25, 1999.  A complete exterior and interior renovation was completed June 2, 2002 .