The carrier will restore the link between the Belgian city and London City airport from 16 January, when four flights a week will commence, with a fifth due to be added from 29 March.
Antwerp is best known as a centre of the diamond industry and major port, but its medieval centre attracts tourists. Return fares are from £139, with timings allowing for weekend breaks.
Luxembourg’s Luxair takes over the route following the collapse of Air Antwerp in June 2021.
Gilles Feith, Luxair chief executive, said: "The opening of this new route from London City to Antwerp is a new venture for Luxair and a chance, once again, to pursue new opportunities.”