SLH was founded in 1577 as a dispensary clinic in Intramuros by Spanish Frey Juan Clemente. It became a hospital in 1578 for patient suffering from leprosy and other diseases.
In 1784, SLH was relocated to Hacienda Mayhaligue, the present site, through a Royal Decree from the King of Spain. A chapel was built and its premises enclosed with stone walls by Frey Felix Huerta in 1859.
The American run the hospital in 1898 as a contagious disease hospital, after 320 years of Spanish governance.
It was only in 1918 that Filipinos started operating the hospital. From 1930-31, insane patients were transferred to National Mental Hospital ( National Center for Mental Health). In 1949, patients with leprosy were located to Tala Leprosarium, now Jose N. Rodriquez Memorial Hospital.
SLH is a referral facility for Infectious/ Communicable Diseases. It is one of the retained special tertiary hospital of the Department of Health (DOH) which is subsidized by the national government.
The hospital has a 500-bed capacity that provides free health care delivery service particularly among the depressed, underserved and underprivileged sectors of the society.
Since 1986, cases of HIV/AIDS were admitted to this hospital.