It was originally established on December 1, 1905, as the Philippine Medical School and later renamed as the UP College of Medicine and Surgery on June 10, 1907.

On September 1, 1910, the 350-bed capacity hospital was opened to the public for health care delivery and clinical instruction and training of medical students.

Thereafter, UP was reorganized into the University of the Philippines System to effect institutional unity, while allowing decentralization of authority and autonomy of the component units through Presidential Decree No.

4, issued by then UP President Edgardo Angara on October 22, 1982, the UP Health Sciences Center was renamed as the University of the Philippines Manila and it became the second autonomous unit of the UP System.

In 2013, UP Manila was badly criticized when Kristel Tejada, a 16-year-old behavioral sciences student, committed suicide because she couldn't pay for her tuition fee for the second semester and was left with no choice but to drop out of school.

[9] Later that month, the Department of Health assigned the Philippine General Hospital as COVID-19 referral center for Metro Manila.

To make room for COVID patient wards, PGH temporarily suspended outpatient and elective surgery services and offered teleconsultations instead.

Through the years, PGH workers also protested against low salaries, job contracting,[19] delayed hazard pay and COVID-19 benefits,[20] insufficient equipment, and budget cuts.

[20] To address the lack of funding and equipment, several UPM units developed different COVID-19 technologies, including the GenAmplify™ COVID-19 rRT-PCR Detection Kit; OstreaVent II; Mechanical Ambu Bag Insufflator; Ginhawa Ventilator; SIBOL innovations such as the RxBox-Telemetry, SIBOL Telepresence, Powered Air-Purifying Respirator, SaniPod, E-Steth Project, and Ultraviolet Irradiation Cabinet; UP Manila Bayanihan Na!

Employee Symptoms Tracking System (BESTS); and PGH Bayanihan Center Current Inventory Levels and Donations Tracker.

Both library buildings were permanently closed in 2016, after they were endangered when the foundation of the nearby under-construction UP College of Medicine Academic Center sank.

In 2019, a PGH polyclinic named the Philippine General Hospital Satellite for Sports Medicine and Wellness (PGH-SSMW) was opened to serve the 2019 Southeast Asian Games.

[35][36] It will be eventually expanded into a full hospital to serve the New Clark City, alongside future branches of the College of Medicine and the National Institutes of Health in the upcoming UP campus in the area.

[36] However, the construction of PGH Diliman is facing scrutiny due to its impact to a protected forest area and its prioritization over upgrade of the current Manila facility.

The Philippine General Hospital and National Institutes of Health also form part of the university as training and research centers.

An applicant for the Doctor of Medicine program can enter through direct entry at Learning Unit 1, where only high school graduates from the top male and female UPCAT scorers are accepted, or lateral entry at Learning Unit 3, where college graduates who passed the National Medical Admission Test (NMAT) are accepted.

[48] Students who will benefit from this program are expected to render a one-year "return service" to the Philippines for every cash grants he or she receives.

[48][51] In research, UP Manila has been pursuing its mandate by generating and disseminating knowledge and technologies that can effectively contribute to the improvement of the quality of life of Filipinos.

Its research outputs have greatly influenced the thrusts and directions of national health care programs and have been used as basis for policy formulation and implementation.

[56] Researches which exerted the biggest national impact on Philippine health care include several research-based program recommendations generated through the national surveys on blindness and the studies on Hepatitis B, diarrhea, and common parasitic infections, which were adopted by the Department of Health; commercialization of five herbal medicinal formulations (lagundi, yerba buena, tsaang gubat, sambong and akapulko); textbooks and instructional manuals which are also used by other academic institutions; and the performance evaluation of PhilHealth, the country's national health insurance program.

This initiative was intended to streamline and harmonize the process of ethics review, maximize the utilization of human and institutional resources, and provide a supportive and enabling environment for research in the university.

Prior to the establishment of the UPMREB, the different component panels already had existing standard operating procedures (SOPs), now superseded, which were used as the basis for the content of this current integrated manual.

One important contribution of this integration is the opportunity to closely review the old SOPs towards a more practicable set of procedures guiding UPMREB work.

UP Manila consistently achieves the highest national passing rate among all health universities and colleges in the country, a feat which has been recognized many times by the Professional Regulation Commission.

[57] UPM has been distinguished as top performing school in medicine, nursing, pharmacy, dentistry, and rehabilitation sciences licensure examinations.

Fe del Mundo, a pediatrician, was known as the first woman to be admitted as a student in Harvard Medical School, and was the founder of the first pediatric hospital in the Philippines.

Other notable UP Manila alumni includes Martino Abellana, a renowned Cebuano painter, and Trinidad Tarrosa-Subido, a linguist and poet.

Political figures who were graduates of UP Manila include Jinggoy Estrada, a Philippine Senator, and Enrique Manalo, who served as the Undersecretary for Policy of the Department of Foreign Affairs.

In film, entertainment, and television, UPM is represented by comedian actress Maricel Laxa, and Vinci Montaner, a founding member of the band Parokya ni Edgar.

[84][85] Some people, such as Diosdado Macapagal, the 9th Philippine President, Paz Latorena, a writer, and Grace Poe, a senator, attended UPM but did not graduate.