Perhaps in no other constituent university of the UP System is the history of UP more closely bound than in UP Manila, being its birthplace in June 1908 at the Ermita-Padre Faura campus. On this day, UP was established by Act 1870 of the Philippine Legislature to provide advanced instruction in literature, philosophy, science and arts and give professional and technical training to every qualified student. The current 10-hectare campus where UP Manila now stands was where the university spent its pioneering and formative years during the American colonial period. 

One of the first colleges that comprised the University was the College of Medicine (CM), which was enacted in 1905 as the Philippine Medical School. With UP's birth in 1908, the School was renamed College of Medicine and Surgery and included as one of the colleges. 

In 1907, Philippine Commission Act 1688 dated August 17 created thePhilippine General Hospital and on September 1, 1910, the hospital opened its doors to the public with 300 beds. PGH was eventually linked formally with the CM, with its dean becoming the PGH director. 

The College of Public Health (CPH), College of Pharmacy (CP) and the College of Dentistry (CD) started as units of CM and eventually became full-fledged colleges in 1932, 1935 and 1948, respectively. 

Severely damaged by World War II, the university continued to hold classes in makeshift rooms. After the war, the university transferred to the Diliman campus in 1948, leaving behind CM, CPH and CD. In 1948, the Board of Regents established the College of Nursing following efforts exerted by visionary leaders of the nursing profession to create a school of nursing in UP. 

At the 894th meeting of the Board of Regents on October 28, 1977 and through Presidential Executive Order No. 519 dated January 24, 1979, the Health Science Center was created and recognized as an autonomous campus of the UP System. The Center primarily aimed to provide leadership in education, research and services that will redound to health care of the highest quality. The then existing units related to the health sciences constituted the Center, with the College of Arts and Sciences Manila transformed into a full-fledged unit and made part of the Center. 

Through the years, additional colleges, institutes and units were established, such as the School of Allied Medical Professions now the College of Allied Medical Professions (1962), Institute of Ophthalmology (IO, 1965), Institute of Health Sciences now the School of Health Sciences (1975) and the National Teacher Training Center for the Health Professions (1975). 

The Comprehensive Community Health Program in Bay, Laguna and the Anesthesiology Center in the Western Pacific were created in 1965 and 1969 respectively, but were abolished in 1988 after an exhaustive review. 

On October 22, 1982, the Center was renamed UP Manila by virtue of Presidential Executive Order No. 4. In 1988, the Institute for Socio-Biomedical Research (ISBMR) was created to serve as a common administrative and research facility for UP Manila's research units. In 1995, three more units were established to enhance UP Manila's excellence as a center for academic training, research and development - the School of Distance Education, the Graduate Office, now theNational Graduate Office for the Health Sciences, and the Institute of Biotechnology and Molecular Biology (IBMB). 

With the creation of the National Institutes of Health (NIH) on January 26, 1996 to promote the conduct of health research and lead in the utilization of its research findings, the IO, ISBMR and IBMB were made its initial components. A few years after, several other component institutes were created, such as the Institute of Pharmaceutical Sciences, Institute of Child Health and Development, Institute of Human Genetics, Institute of Health Policy and Development Studies, and Ear Institute.