Dozens of buildings, including the City Square water wall and Brunetti's cafe will be demolished within the next year to make way for the Metro Tunnel.
The Port Phillip Arcade and the strip of fast-food outlets, banks and souvenir stores along the bottom end of Swanston Street are all scheduled to go before early 2018.
Nearby City Square is set to be closed for the construction of an enormous shaft, which at 96 metres by 36 metres will be almost as large as the square itself.
The John Mockridge Fountain – the water wall along Collins Street often decorated with messages written from fallen leaves – will be demolished.
Eight other public artworks will be removed and put into storage, including the Burke and Wills monument which is being sent off for restoration and Larry La Trobe, the cast metal statue of a dog.
The wooden "Warin the Wombat" statue and Victorian of the Year plaques will be relocated.
The popular Brunetti cafe will disappear from City Square by April.
Co-owner Yuri Angele said he had been told that the venue needed to close by March 31.
"We are very disappointed but at the same time we sort of understand that there needs to be better infrastructure," Mr Angele said.
Melburnians could be without a CBD Brunetti location for four about months, as the replacement store, at 250 Flinders Lane, is not scheduled to open until August 1.
More than a dozen warehouses will also be demolished in an industrial pocket West Melbourne, including Laurens Hall, a wedding reception and function venue.
Laurens Hall owner Charles Scott said the contents of the venue, which has hosted about 100 marriages in the past two years, would be auctioned in April.
Mr Scott, 61, said he also lived at the site, so was being made homeless and jobless by the impending demolition.