Historically starting at the Melbourne CBD at Princes Bridge as St Kilda Road and heading south through the Melbourne Arts Precinct, today Nepean Highway is declared to commence at St Kilda Junction as St Kilda Road and heads in a southerly direction until it reaches the intersection with Carlisle Street (prior to the widening in the late 1960s this section was formerly known as High Street[6]), where it changes name to Brighton Road and heads in a south-easterly direction until it reaches the intersection with Glen Huntly Road in Elsternwick, where it changes name again to become Nepean Highway proper.

In 1984 conversion of the seven kilometre section between Cochrane Street, Elsternwick and South Road, Moorabbin to a dual carriageway was completed.

It is reduced to six lanes at Moorabbin, passing through Cheltenham and Mentone, and then to the 60 km/h or 70 km/h four-lane single carriageway after the roundabouts at Mordialloc.

After passing through Mount Martha, the highway runs parallel to the Mornington Peninsula Freeway, before turning toward the town of Dromana.

Anthonys Nose is a point, or escarpment located on the southern shore of Port Phillip Bay, between Dromana and McCrae.

Originally known as Arthurs Seat Road, it was built in the 1850s to provide a road (originally a crude sandy track) from the farms (owned by Jude Roberts) south of Melbourne and link the city with its southern bay settlements and sea defences at Point Nepean.

Transurban, in their Response to the Eddington Report, July 2008,[17] believe a north–south corridor from the Hume Freeway and Metropolitan Ring Road to the Nepean Highway south of Glen Huntly Road, Elsternwick, generally via the Hoddle Highway corridor, deserves attention.