Part of Ingram Street, from Queen Street to Hanover Street, will be shut all day on Sunday and diversions put in place as bulldozers continue to tear down the former Bank Of Scotland offices.
The latest road closure is taking place so construction workers can safely remove an eight-storey segment of the 1960s building, which is across from the Gallery Of Modern Art.
Bulldozers began tearing down the 11-storey building, which lay empty for four years, in February.
Once it is flattened, an eight-storey retail and office complex will be built.
A spokeswoman from BAM Properties, which bought the site in 2010 for £7.5million, said: "We have a temporary road closure in place for safety reasons.
"There will be pedestrian access, but no vehicles will be allowed.
"We have posted letters to people living nearby and let shops and cafes know what's happening. The bus companies also know the road is closing and there will be a diversion route for them."
A traffic notice sent out by Glasgow City Council said the road was being shut to "facilitate demolition works" and that "delays may be experienced".
A council spokesman said: "The contractor asked for permission to close the road with a view to public safety.
"By carrying out the work on Sunday, disruption to traffic will be minimised."
The plan to transform the Merchant City eyesore was first reported in the Evening Times in September 2011.
The demolition is due to be complete in six weeks, with the whole project's finishing date set for 2015.
The BAM Properties spokeswoman added: "Once the building is gone workers will begin laying foundations. People will start to see some major changes in late summer or early autumn when it starts to take shape."
The new complex will create 143,000sq ft of offices and 20,000sq ft of retail space, with space for up to 1200 workers.
Ingram Street is already home to prestigious shops such as Ralph Lauren, Agent Provocateur, Cruise and Jigsaw.
It is hoped this latest retail space will attract further big names to the area.