The 546 operated from Heidelberg along Heidelberg Rd through Ivanhoe, Darebin, Alphington, Fairfield, Westgarth and Clifton Hill to the corner of Smith St and Victoria Pde in Collingwood. In the early 90s the route was truncated to Clifton Hill, however in 1996, it was extended from Clifton Hill though Fitzroy and Carlton past Melbourne University to Victoria Market.
The 546 was operated by Reid's Metropolitan services from their depot in Northcote until their takeover by the Dysons group when services were then operated from their Bundoora depot.