The history of the Boston Public Health Commission dates back to 1799 when an ordinance was passed to establish a Board of Health to "examine into all causes of sickness, nuisances, and sources of filth that may be injurious to the health of the inhabitants of the town of Boston." Included in the history of the Commission is the history of the Department of Hospitals, particularly Boston City Hospital, which opened in the South End in 1864 and was established to provide quality medical care to the city's residents regardless of their ability to pay. Both of these institutions functioned as separate entities until 1965, when the Hamlin Report recommended the merger between the Department of Health and the Department of Hospitals, which would respond to the rapidly growing health care reform movement in the country and improve the quality of care in the city.

From its beginning, the mission of the Boston Public Health Commission has been to promote and preserve the health and well-being of the city's residents. Examples of early programs and services include establishing neighborhood health centers, instituting school inspections, setting up the first diabetic clinic in the country, and providing nurses' visits. In order to expand its effectiveness, it became affiliated with Harvard, Tufts, and Boston University, instituted a field service program, and collaborated with other health and social welfare agencies throughout Boston. At the time of the 1965 merger, the Department of Health and Hospitals was organized into four categories: General Services, Medical Services, Environmental Sanitation, and Local Health Services.

Throughout its history, Boston City Hospital sought to provide quality health care to residents regardless of their socioeconomic status through its strong residency programs, the depth of its medical research especially in the field of Pediatric AIDS, and its emergency medical services. At the time of the merger with the Department of Health, the City Hospital was made up of 28 buildings all of which were built between 1864 and 1940. These buildings also included the Boston Specialty and Rehabilitation Hospital and Long Island Hospital. In addition, Boston City Hospital was the primary teaching hospital in the city and was affiliated with Harvard, Tufts, and Boston University Medical Schools. By 1972, the combination of the condition of the hospital’s physical plant, the City's financial problems, the changes in health care delivery, and the innovations in medical technology made it clear that re-evaluation was necessary. In response to these problems, the hospital became solely affiliated with Boston University Medical School, began reducing its licensed capacity of 1,200 beds, and started developing plans to replace its buildings. In 1977, as part of its plan for change, the hospital opened the Ambulatory Care Center. However, it was unable to replace other buildings because of financial constraints.

During the early 1990s, several attempts were made to improve and modernize the health care system in Boston while keeping Boston City Hospital and the Boston Specialty and Rehabilitation Hospital from permanently closing their doors. Regardless of these efforts, economic considerations, further advances in medical technology and health care delivery, and the changing needs of the communities served by the Department of Health and Hospitals required an in-depth study. In 1994, the Mayor's Special Commission on Health Care (McGovern Commission) was created. The culmination of this study was its recommendation in 1995, which proposed the merger between Boston City Hospital and Boston University Medical Center. By consolidating these two institutions, the original mission of Boston City Hospital to provide quality health care to residents regardless of their financial status was assured of continuing through the Boston Medical Center. Also in 1996, Mayor Thomas Menino established the Boston Public Health Commission (BPHC), an independent public agency that is responsible for both responding to the city’s health problems and serving as the City’s Board of Health.

As the city agency whose responsibility it is to make Boston a healthier place in which to live and work, the Commission was successful in instituting a city-wide ban on smoking in public buildings, and held meetings that were specifically designed to respond to health concerns of every neighborhood in the city. In 2007, it launched campaigns to increase awareness of both health and safety issues including cancer, the continuing risk of AIDS, and violence prevention; and it began making efforts to close the gap in racial, ethnic, and socioeconomic health disparities.