[5] In conjunction with McIvor Highway, it provides an important link between Melbourne and Bendigo.

It forms a significant freight route providing access to markets and ports in Melbourne and the rural primary production areas of the Murray Valley and southern New South Wales, and serves a number of agricultural and tourism-related industries along its length.

Northern Highway commences at the state border with New South Wales as a continuation of Cobb Highway into Victoria and heads in a southerly direction as a two-lane, single carriageway rural highway through the western part of the regional town of Echuca, running concurrent with Murray Valley Highway for a short period, before continuing south through flat open country through Rochester, Elmore and Heathcote, then traverses moderately hilly terrain through Kilmore and Wallan, before eventually terminating at the interchange with Hume Freeway a short distance south of Wallan in Beveridge.

Northern Highway was declared a State Highway on 1 July 1925,[3] cobbled from a collection of roads from Bendigo through Elmore and Rochester to Echuca (for a total of 55 miles), subsuming the original declaration of Bendigo-Echuca Road.

In the 1947/48 financial year, its southern end was rerouted south of Elmore: instead of running to Bendigo, it was extended further south via Heathcote to meet Hume Highway at Kilmore,[12] subsuming the original declarations of Heathcote-Elmore Road and Kilmore-Heathcote-Bendigo Road as Main Roads; the previous alignment of Northern Highway from Elmore to Bendigo was subsumed into Midland Highway.