The German city is the airline’s third destination from Antwerp after London City airport and Manchester airports.
VLM Airlines managing director Johan Vanneste said that three flights a day would be operated between the two cities using a Fokker 50 aircraft.
"The opening of our third destination from Antwerp is of great importance to Antwerp International Airport, which once again can play its trump card of being a comfortable and fast gateway to major European cities," he said.
Mr Vanneste added that, since the European Central Bank established its seat in Frankfurt, the importance of the city as a major financial centre "has only increased".
Passengers can expect the flight to last for one hour and 20 minutes.
VLM Airlines launched a new flight to Eindhoven from London City Airport on January 12th.