The original Edinburgh Infirmary, Hospital for the Sick Poor, Physicians' Hospital, or Little House was located at the head of Robertson's Close. A town house was rented from the Town Council and patients were admitted to the four beds then available from 6 August 1729. In 1936 a Royal Charter was obtained under the name The Royal Infirmary of Edinburgh. A 228-bed purpose-built hospital designed by William Adam soon followed, and the first patients were admitted to it in 1741. It was located between what are now Infirmary Street and Drummond Street. Two further surgical hospital buildings were added in 1832 and 1853. Due to overcrowding throughout this so-called High School Yards site, David Bryce was commissioned to design a new hospital and in 1879 the Infirmary moved to Lauriston Place, its main building conforming to the pavilion style of surgical and medial ward arrangement.

The original appeal for funds was led by the Royal College of Physicians of Edinburgh, making the Royal Infirmary of Edinburgh the first voluntary hospital in Scotland. Its charitable subscribers were formed into a Court of Contributors who elected annual Managers drawn from the main occupational and professional groups of the City. This form of funding and administration, with few modifications, continued until 1948 when the National Health Service was founded. Thereafter the Infirmary, including the Royal Maternity and Simpson Memorial Hospital which amalgamated with it in 1926, became the Royal Infirmary of Edinburgh and Associated Hospitals group, with its own Board of Management within the South Eastern Regional Hospital Board. Further administrative changes occurred in 1974, 1994 and 1999, over which time the hospital was successively part of the South Lothian District and then a Unit of Lothian Health Board, a Trust in its own right, and it is currently part of Lothian University Hospitals NHS Trust.

Concern over the Lauriston site was first expressed in 1946, when it was felt that the current Royal Infirmary buildings were insufficient to meet the needs of the new National Health Service. Various plans were put forward, including demolition and rebuilding of the existing site, and construction of a brand new Royal Infirmary on a greenfield site, along with another new southern general hospital. Throughout the 1950s and 1960s a number of options were discussed, but the decision was eventually made to rebuild at Lauriston in a series of phases which aimed to minimise disruption to patients and staff. Work was repeatedly delayed however, due in part to financial issues and also to the fact that the Secretary of State for Scotland declared that the listed buildings could not be demolished, and it was not until 1981 that the first phase of rebuilding was completed. Again however this plan did not come to fruition, and in the late 1990s work was begun on a new Royal Infirmary at Little France which would also replace the Simpson Memorial Maternity Pavilion, the Princess Margaret Rose Orthopaedic Hospital and the City Hospital. Although still under construction and not due for full completion until 2003, the first patients moved in in January 2002 as the PMR closed.