The first hospital in Regina was actually a house. Mrs. Mary E. Truesdell operated a private hospital in her house from 1889 to 1897. Although it only had beds for four men and two women, the little hospital was badly needed in the community, as the only ‘real' hospital nearby was located in Medicine Hat . Regina was still suffering at the time from a lack of adequate water and sewer lines, and only one scavenger serviced the town. Epidemics of infectious disease were still commonplace; the 1892 typhoid epidemic was one of the worst disease pandemics to hit the town since its founding, and Mrs. Truesdell's hospital treated many patients during that time.

By 1895 the Regina Local Council of Women was campaigning for the establishment of a private hospital. Their lobbying paid off in the form of Cottage Hospital, a private hospital staffed by members of the Victorian Order of Nursing. The hospital, funded by public subscription and located in a rented house, soon could not meet public demand, and so the Victoria Hospital was opened on the south-west corner of Hamilton Street and 14 th Avenue in 1901. The Victoria Hospital could serve 25 patients, a vast improvement over the 7-bed Cottage Hospital. The Victoria Hospital was initially funded by public donations, but public demand soon outstripped this source of funding. After several attempts to get more money from the government or from city council, Victoria Hospital was taken over by the city. It became known as the Regina General Hospital in 1907.

The Regina General Hospital began construction on a new building in 1909. This building is the nucleus of the current-day Regina General Hospital . The original structure was designed by the Regina-based architectural firm of Storey and Van Egmond. Originally, the building had a 100-bed capacity, cost over $100,000 and took two years to complete. Additions were built onto the main structure in 1913 and 1927, upgrading the facility to a 410-bed capacity. Additional construction took place in 1949 – upgrading the building's capacity to 800 beds - and again in 1966, with a final addition constructed in the late 1990s.

The Regina General Hospital was not Regina 's only hospital in the early years, however. The forerunner to the Pasqua Hospital , the Regina Hospital (later the Grey Nuns Hospital ), opened in 1907. Eventually both the Regina General Hospital and the Grey Nuns Hospital were sold to the provincial government.