The Flybe service from George Best Belfast City Airport to John Lennon Liverpool will be axed at the end of the month.
The Belfast to Doncaster flight will also cease on 30 October.
The airline operates three return flights daily from Belfast to Liverpool and one to Doncaster.
Shares in Flybe plunged by 36% on Wednesday after it said there had been a "significant slowdown in sales" across its UK domestic network.
In May, the Exeter-based airline warned of the impact of the spending slowdown, as well as unveiling a £3 fuel surcharge for all flights which came into force last month.
The airline told BBC Online: "Flybe can confirm that with effect from 30 October 2011 it will cease operating services from George Best Belfast City Airport to Liverpool and Doncaster.
"Flybe carefully reviews the viability of all its 200 plus routes looking not only at passenger numbers but also at external cost pressures such as the extortionate Air Passenger Duty system being levied on the domestic aviation sector where its passengers pay twice as much tax as Europe-bound travellers.
"This ongoing monitoring of our routes enables us to both increase regularity where demand exists, but also highlights when passenger numbers make a flight economically and environmentally harder to justify."
Flybe's other 16 direct services from Belfast which include flights to London, Gatwick, Birmingham, Manchester, Edinburgh and Southampton are not affected.
The company has unveiled its second profits warning in five months. Shares fell 40% to 60p - a total fall of 80% on the flotation price of 295p in December 2010.