In 1879 the City of Hamilton purchased four acres of land located north of Barton Street between Victoria Avenue and Wellington Street. The location wasn't particularly central to the City at that time but was considered to be close enough and the price was right. The City then drained, levelled, graded, sodded and fenced the property. The initial hospital, opened in 1882, consisted of three buildings. A main building facing Barton was a three story brick structure with a mansard roof. It housed the administrative offices and the dormitories for nurses and other staff. The kitchen was in the basement. Two other buildings, separate from the main building, housed the public wards, the east wing for male patients and the west wing for female patients. They were connected to the main building by external corridors. The hospital featured fireplaces in the wards, dumb waiters and speaking tubes. Another one story brick building was soon added to the main building to house the laundry and the morgue. A separate frame building was built as an isolation ward.
Following the example of many other municipal hospitals in Ontario, a training school for nurses was opened in 1890. It began as a two year and expanded to a three year programme with formal instruction given by the head nurse and the physicians. It was essentially an apprenticeship where the young women worked on the wards from 7 am to 7 pm and often later with one half-day off a week and three weeks vacation. Initially they lived in rooms within the main building but later a nurses residence was built on the hospital grounds. There were two graduates in the first class. The Hamilton General Hospital School of Nursing continued to graduate nurses until 1973 when Mohawk College took over the programme.
Services at the General continually expanded. A maternity unit opened in 1892. In 1938 the first cancer clinic in Hamilton was established at the General. It operated until 1949 when it was taken over by the Ontario Cancer Treatment and Research Foundation.
In 1962 the Hamilton General Hospital amalgamated with the Nora-Frances Henderson Convalescent Hospital and the Mountain Hospital to become a single corporation called the Hamilton Civic Hospitals. In 1997 Hamilton Civic Hospitals amalgamated with Chedoke-McMaster Hospitals to create Hamilton Health Sciences.