The original Edinburgh Infirmary, Hospital for the Sick Poor, Physicians' Hospital, or Little House was located at the head of Robertson's Close, in Edinburgh. 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, Edinburgh. 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. Concern over the Lauriston site began to be expressed first 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 (PMR) and the City Hospital. Full completion occurred in 2003, although the first patients moved in in January 2002 as the PMR closed.

Instrumental in the founding of the RIE in 1729 was the Royal College of Physicians of Edinburgh, itself founded some 90 years earlier. In the seventeenth century, Edinburgh physicians had started holding meetings in their own homes to discuss medical practice and standards and their regulation and improvement. Sir Robert Sibbald, an eminent physician and noted historian, was a member of this group. Sibbald had the opportunity of petitioning King Charles II, who granted the Royal College of Physicians of Edinburgh its Royal Charter in 1681. Thus it is that Sir Robert is generally accepted to be the founder of the Royal College of Physicians of Edinburgh.

The 'Baffin' was built to the design of William Scoresby (1789-1857). The ship was the first whaler to be built in Liverpool and was launched on 15th February 1820, having a successful first voyage and in 1822, Scoresby mapped the East coast of Greenland.