It is one of several medical facilities established in the state during the early 20th century by the Franciscan Missionaries of Our Lady, a Roman Catholic religious order based in Calais, France.

In 1945, Isenberg was injured in an automobile accident and was treated at another Franciscan hospital, Our Lady of the Lake Medical Center in Baton Rouge.

In 1958 a four-story addition was constructed, doubling the hospital's capacity to 110 beds and allowing expansion of surgery, emergency services, laboratory and radiology departments.

The new complex was built during the years 2009-2011 and officially opened on Ambassador Caffery Parkway, on the city's south side, in July 2011.

News media accounts and the hospital's website describe the new Our Lady of Lourdes Regional Medical Center as the largest construction project in the city's history, incorporating 396,000 square feet of building space, 45 acres of land and employing over 1,200 persons, including over 400 active physicians.