A subdistrict of the Lower Ninth Ward District Area, its boundaries as defined by the City Planning Commission are: St. Claude Avenue to the north, St. Bernard Parish to the east, the Mississippi River to the south and the Industrial Canal to the west.

The City Planning Commission defines the boundaries of Holy Cross as these streets: St. Claude Avenue, St. Bernard Parish, the Mississippi River and the Industrial Canal.

The original campus at 4950 Dauphine Street was destroyed by Hurricane Katrina on August 29, 2005, allowing the school to use FEMA funds to relocate to the Gentilly neighborhood.

In August 2012, a portion of the old campus was sold to Perez Architects, which proposed building a 180-unit riverfront apartment complex and immediately applied for a zoning change to increase the height limitations.

Opposition from residents arose because the proposed development would negatively impact the historic nature of the neighborhood and create increased density and traffic congestion.