Starting next March, Brussels Airlines will operate the service five times a week.
The announcement has been welcomed by Northern Ireland business leaders and tourism officials.
The route was previously offered from Belfast International, but stopped many years ago.
The new flights will operate on Monday, Wednesday, Thursday, Friday and Sunday.
"On a weekly basis we will offer close to 1,000 seats on the route," Brussels Airlines chief commercial officer, Lars Redeligx said.
"Belfast is an important touristic, administrative and economic destination."
The airline is part of the Lufthansa Group.
Belgium's national airline is to begin a new flight between Brussels and George Best Belfast City Airport.