The Children's Hospital officially opened in June 1909 with two 20 bed wards, an operating theatre, an outpatient's department, a staff residence and an administration block. By 1911, an infant's pavillion of 20 beds and isolation ward of 12 beds had been added.

The original staff comprised a Resident Medical Officer, a Matron, 3 nursing sisters, 6 staff nurses, 5 probationers and a dispenser who also acted as a clerk.

The hospital was registered as a training school for nurses with the Australian Trained Nurses Association from its time of opening, becoming a general training school for nurses in 1927.

The name of the Children's Hospital was changed to that of Princess Margaret Hospital for Children on 27 January 1949.

Previously the Children's Hospital, the hospital's name was changed to the Princess Margaret Hospital for Children on 27 January 1949.

In 1959 it became a teaching hospital with the establishment of the Faculty of Medicine at the University of Western Australia.

A new outpatients building opened in October 1964 and a main ward block was added in 1969. In the same year, the Princess Margaret Children's Medical Research Foundation was established.

In 1983, the Patient Services' Building, Stage I, was opened and in 1987 the Stage II building was completed.