The school's campus is located at the picturesque St. Charles Avenue in uptown New Orleans, near the Audubon/University District.

De La Salle High School is named after St. Jean-Baptiste de La Salle, the founder of the Institute of the Brothers of the Christian Schools, (the "French Christian Brothers").

De La Salle High School opened in September 1949 with a freshman class of 74 boys.

Classes were initially held in a large old home (which also served as the residence for the De La Salle Brothers) on Pitt Street, but, in 1951, De La Salle High School moved to the present building on St. Charles Avenue.

De La Salle High School built the Shane and Holley Guidry Batting facility for baseball and softball.