Robert Mapplethorpe established the not-for-profit Robert Mapplethorpe Foundation on May 27, 1988, some ten months before his death, to protect his work, to advance his creative vision and to promote the causes he cared about. Serving as the first president on a five-person board of trustees, he established an initial mandate of furthering the recognition of photography as an art form of the same importance as painting and sculpture. During the last weeks of his life, he added the second mandate of supporting medical research in the area of AIDS and HIV infection. In keeping with Mapplethorpe's wishes, The Robert Mapplethorpe Foundation has funded numerous publications on photography, supported exhibitions at various art institutions, and provided grants—in the form of funding or gifts of original Mapplethorpe works—to art institutions ranging from the world's major art museums to small university galleries. In 1993, the Foundation provided a major gift to the Solomon R. Guggenheim Foundation to create the Robert Mapplethorpe Gallery and inaugurate the Guggenheim Museum's photography department and program.

In the field of HIV/AIDS research, the Foundation has provided study grants to university research centers and established important medical facilities and programs, such as the Robert Mapplethorpe Laboratory for AIDS Research at Harvard Medical School in Boston, the Robert Mapplethorpe AIDS Treatment Center at Beth Israel Medical Center in New York, and the Robert Mapplethorpe Center for HIV Research at St. Vincent's Hospital and Medical Center of New York. The Foundation has also provided substantial financial support to the American Foundation for AIDS Research (AmFAR), which was one of the first recipients of Mapplethorpe's generosity during his lifetime. The Foundation continues to support research initiatives at various levels based on approved grant applications for research-based facilities and organizations.

In addition to its charitable work, the Foundation maintains Mapplethorpe's artistic legacy by preserving his archive of works, strictly maintaining the editions he established during his lifetime, facilitating loans of his photographs, and placing his work in important museum collections around the world.