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.