For tens of thousands of years it was used as a food and tool source sustainably by the Wurundjeri people, Indigenous Australians of the Kulin nation alliance, who spoke variations of the Woiwurrung language group.

The creek rises on the northern urban fringe of Melbourne north of the suburb of Epping, following a general southerly route and meeting the Yarra at Alphington.

Formerly an intermittent stream, increased stormwater runoff with urbanisation of the Darebin Creek catchment has resulted in permanent water flow.

The Darebin Creek's headwaters begin in Wollert, South Morang and even as far as Woodstock where they flow in a roughly southerly direction before meeting north of Epping.

Excellent examples of remnants of Melbourne’s early agricultural history can be seen within the Darebin Parklands in Alphington and Ivanhoe.