The campus was designed by Louis Kahn. Salk had sought to make a beautiful campus in order to draw the best researchers in the world. The entire 27 acre site was deemed eligible by the California Historical Resources Commission in 2006 for listing on the National Register of Historic Places.

Jack McAllister was the building's supervising architect and a major design influence on the structure that consists of two symmetric buildings with a stream of water flowing in the middle of a courtyard that separates the two. The buildings themselves have been designed to promote collaboration, and thus there are no walls separating laboratories on any floor. There is one floor in the basement, and two above it on both sides. The lighting fixtures have been designed to easily slide along rails on the roof, in tune with the collaborative and open philosophy of the Salk institute's science. The basement also houses the transgenic core. Tenured professors also receive a study that has a view of the Pacific ocean. A library that houses current periodicals, some books and computers is located on the ground floor of the east end of the North building. An auditorium and the Trustees' Room are located in the basement of the north and south wings of the institute.