The old main building was built in 1845, and is considered by the National Park Service to be the best remaining antebellum hospital in the United States.

[8] The structure was strategically placed between the wharves of Louisville and Portland, with a "beneficial effect of a view of the water, and the impressions and associations it would naturally awake in the minds of men whose occupation were so intimately connected with it.

"[3] It was a "cutting edge" facility, with indoor plumbing and an air circulation system that helped prevent infections.

[10] The patients at the Louisville Marine Hospital were usually victims of disease, temperature extremes, and mechanical deficiencies of the era's naval technology.

[3] During the American Civil War, along with Jefferson General Hospital, it formed the foundation of Louisville health care for wounded soldiers, both Union and captured Confederates.

[4][7] That year, the hospital received a $375,000 Save America's Treasures grant from the National Park Service to repair its roof and exterior.

[5][15] Small buildings that once housed a boiler and a parking structure were razed to reflect the original design.

[10] In 2007, the basement, which formerly held boilers, was proposed to be used as a 3,450-square-foot (321 m2) multi-use ballroom and rented out for parties and other special events, and the building's ground floor as an interactive center featuring hospital history and artifacts.

[16] Also in 2007, discussions were held with the University of Louisville about placing a Community Health Center in the historic building.

[10] However, efforts to raise money to renovate the interior of the building remained unsuccessful as late as 2018, although the first floor was in use as a meeting space.