Named after the Maribyrnong River, the road forms the boundary between the suburbs of Moonee Ponds and Ascot Vale for its entire length.

Previously, road and tram traffic crossed the river on separate bridges: the former Raleigh Road bridge on a dog-leg alignment just to the north of the current bridge for vehicular traffic (designed by John Monash) dating from 1911,[2] and a timber trestle bridge solely for trams crossing the river on a direct route dating from 1940, to serve the explosives factories on the western side of the Maribyrnong during WWII.

[4] However, the council pushed for a replacement due to safety concerns, after reports of pedestrians falling through the trestles and drowning.

Maribyrnong Road was signed as Metropolitan Route 38 between Moonee Ponds and Ascot Vale in 1965.

Due to the increasing amount of pedestrian and bicycle traffic over the Raleigh Road bridge, a $2.7 million project to widen the paths to 3 metres on each side of the bridge was started early January 2021, completed nearly two months later at the end of February 2021.