At its opening on 1st May 1879 Edinburgh Royal Maternity and Simpson Memorial Maternity Pavilion became the first building in Edinburgh to be planned as a maternity hospital. As early as 1756 provision had been made for four maternity beds in the Royal Infirmary, and in 1793 the General Lying-in Hospital had been opened at Park House. However it was not until 1879 that money collected to commemorate the contribution of Sir James Young Simpson to obstetrics, ended the numerous moves to makeshift hospitals which had been made over the preceding forty years, and enabled the City to open a purpose-built maternity hospital where the poor could have their children under medical supervision.

Initially the hospital consisted of two lying-in wards, a labour ward, dispensary, kitchens and administrative quarters, as well as quarters for the matron, two house surgeons and seven or eight nurses. In 1895 Lady Tweedale opened the Married Women's Pavilion. This was the west wing originally proposed by the architects MacGiggon and Ross, but postponed in 1879 because of insufficient funds.

Four visiting physicians with their assistants undertook in rotation a three month term of duty. Besides hospital deliveries, medical students or pupil midwives, supervised by hospital staff, attended home deliveries. These are recorded in the Out-Door case books. The 1886 Amendment to the Medical Act made midwifery a compulsory course in the medical curriculum, and in 1890 women students were admitted to the hospital for clinical instruction. The risk of infection was always present and in 1899 the hospital closed because of puerperal septicaemia. Later cases were transferred as quickly as possible to the City Hospital to prevent cross-infection, and in 1924 Dr.Nasmyth donated a new labour ward allowing the separation of infected cases.

By 1910 the hospital was dealing annually with 616 indoor and 1327 district cases, and the hospital authorities were faced increasingly with problems such as lack of operating facilities, unsatisfactory accommodation, inadequate sanitation and gross overcrowding. After World War 1 three maindoor basement flats in Lauriston Park and two flats in Graham Street were acquired to try to meet the increasing demands on the hospital.

Throughout the first quarter of the twentieth century advances were made in obstetrics, pathology and paediatrics. In 1901 a pre-maternity bed was instituted at the hospital. William Ballantyne took a particular interest in the physiology and pathology of pregnancy and James Haig Ferguson furthered the cause of preventative medicine by stressing the benefits of routine antenatal supervision. As a result of his efforts the first out-patient antenatal clinic in Britain was opened in 1915 and in 1926 a postnatal clinic was opened. The Central Midwives Board for England and Wales (established in 1902) recognised the Simpson as a training centre for midwives wishing to practise north of the Border. In 1915 the Central Midwives Board for Scotland was established and the following year the hospital was recognised by them.

Two years after the Notification of Births (Extension) Act of 1915, the Edinburgh Local Authority launched a maternity and child welfare scheme in conjunction with the hospital. Seven antenatal out-patient clinics were opened in Edinburgh with the main consultative centre at the Maternity Hospital, for which the Corporation paid the hospital £200. In 1919 the Local Authority, acting on the recommendation of a Royal Commission report of 1916, arranged with the hospital the establishment of an antenatal out-patient and in-patient venereal disease department.

In 1925 the first assistant paediatrics physician was appointed. With maternal deaths in Scotland reaching a peak of 651 in 1931, a concerted effort was made to combat eclampsia and generally to reduce perinatal morbidity and mortality. This objective was achieved very largely through advances in therapeutics such as the advent of chemotherapy and antibiotics, the work of the national blood transfusion service, and improved anaesthetics.

From as early as 1910 overtures had been made to the Royal Infirmary to alleviate pressure on the Maternity Hospital. Subsequent attempts had also come to nothing until in 1926 a conclusion was reached with the purchase of George Watson's School from the Merchant Company. An obstetrical unit of 150 beds was constructed and at the same time the Florence Nightingale Nurses' Home was built to provide accommodation for the midwives and their pupils. On 1st March 1939 the old Simpson closed and the Simpson Memorial Maternity Pavilion, which was incorporated into the Royal Infirmary, assumed responsibility for maternity services. In the new pavilion the principle of isolation as a means of containing infection was fully implemented and by 1979 the number of beds had increased to 225 while the hazards of childbirth and perinatal mortality had been drastically reduced.

From 1939 to 1948 the Hospital was administered by the Managers of the Royal Infirmary of Edinburgh, from 1948 to 1974 it formed part of the Royal Infirmary of Edinburgh and Associated Hospitals group; from 1974 to 1984 the hospital was part of the South Lothian District of Lothian Health Board. From then on the Hospital formed part of the Royal Infirmary of Edinburgh NHS Trust, now Lothian University Hospitals NHS Trust.