Philippe Couillard, a popular former health minister, confirmed to The Canadian Press he will announce his candidacy on Wednesday in Montreal.
The 55-year-old former brain surgeon, considered a possible frontrunner, could shake up the leadership contest to replace Charest.
Couillard wants the Liberals to better defend Quebecers on key identity issues — such as language and the province's relationship with Ottawa — in order to compete with the newly-elected Parti Quebecois.
Couillard was Quebec's health minister from his election in 2003 until 2008, when he left politics.
Pierre Moreau, a former transport minister and member of Quebec's national assembly, is expected to officially enter the running on Monday.
The province's former finance minister, Raymond Bachand, was the first to announce his candidacy last week.
He was the man behind the province's controversial tuition increases — which were praised by small-c conservatives but bitterly opposed by progressives. The increases were cancelled by the PQ.