Its campus partners are the Murdoch Children's Research Institute and The University of Melbourne Department of Paediatrics, which are based onsite at the hospital.

The hospital was established in 1870,[5] founded by doctors John Singleton and William Smith, in response to their serious concerns about infant mortality in the fledgling city of Melbourne.

Frances Perry was elected as the inaugural president of the committee of management, although she was unsuccessful in imposing a Protestant religious ethos on the hospital.

[8] The management committee influenced patient admissions, often turning away children from wealthier families who they believed could afford private care.

[10] William Snowball was an influential paediatrician at the hospital from 1878 until his death in 1902, working to "improve accommodation and hygiene conditions for children in medical care, training structures for nursing staff, and research into diseases afflicting his patients".

[9] The RCH Auxiliary movement was established by Mary Guthrie in 1922 to coordinate volunteering and fundraising efforts at the hospital.

In conjunction with medical director Vernon Collins and lady superintendent Lucy de Neeve, she oversaw the transition of the hospital "from a charity hospital to an institution that provided medical services of the highest quality, education and training facilities for staff, a research organization in both curative and preventive medicine, and a link with the university".

In 2005, the Victoria State Government announced plans to build a brand new 340 bed home for RCH adjacent to the existing site.

HKS Inc. Architects of Dallas, Texas provided Paediatric Design and Planning Services and consulting engineers Norman Disney & Young.

[32] Each year since 2002, the Elizabeth Turner Medal has been awarded to senior medical or dental practitioners at the RCH who have consistently shown excellence in clinical care over an extended period of time.

[33] The medal is named in honour of Graeme Barnes (Gastroenterology) and John Hutson (General Surgery and Urology) in acknowledgment of their all-round contribution to clinical practice, research, education, and mentorship.