Cyprus Airways will stop serving Manchester from November 1.
The airline currently flies four-times weekly between Manchester and Larnaca, its longest non-stop route.
According to reports, insufficient bookings prompted the decision, exacerbated by increasing costs due to the rising price of fuel.
The Manchester-Larnaca route will continue to be served by Monarch, which flies daily between the two destinations.
Earlier this summer, Cyprus Airways also took the decision to cancel flights between London Heathrow and Paphos from the end of October.