South of Bendigo, where the former highway has been upgraded to freeway-standard, Calder Freeway links to Melbourne, subsuming former alignments of Calder Highway; the Victorian Government completed the conversion to freeway standard from Melbourne to Bendigo on 20 April 2009.

It narrows back to a two-lane single carriageway road and continues in a southerly direction, meeting Mallee Highway at Ouyen, then in a south-easterly direction through Sea Lake, Wycheproof, Charlton and meeting the northern end of Calder Alternative Highway at Marong eventually to the western suburbs of Bendigo, where it widens to a four-lane, dual-carriageway road as it weaves through the rural city, intersecting with Loddon Valley Highway and meeting with Midland Highway, where it narrows back to a single carriageway road and shares a concurrency through south-western Bendigo, widening again to a dual carriageway through Kangaroo Flat to eventually meet the southern end of Calder Alternative Highway at an interchange in Ravenswood.

Calder Freeway passes Harcourt - where the shared concurrency with Midland Highway ends, as it travels in a south-westerly direction to the major regional centres of Castlemaine, Ballarat, and Geelong - and continues in a south-easterly direction past Elphinstone, Kyneton, Woodend and Gisborne, to reach the western suburban fringe of Melbourne.

It continues in a south-easterly, and then easterly, direction past Calder Park Raceway and Keilor, before eventually terminating at an interchange with Tullamarine Freeway at Airport West.

Originally, Calder Highway ran through northwestern Melbourne as an undivided highway, ultimately through Niddrie as Keilor Road and terminating in Essendon; traffic continued south along Mount Alexander Road to reach central Melbourne.

[citation needed] In 2008, VicRoads completed the widening of the Calder Freeway from the Western Ring Road to Melton Highway.

A further upgrade completed in 2012 resulted in a new interchange at Kings Road (the freeways's urban / metropolitan limits) and closure of three at grade intersections in the area.