Among those affected were a service to Leeds Bradford from Belfast City this morning and the return flight to Northern Ireland.
Flybe's other flights from Leeds Bradford today are going ahead as planned but there have been cancellations at several other UK airports.
Now the carrier has blamed pilot holidays and 'seasonality' - it began flying the summer schedule this week - for the chaos, which has affected five per cent of its timetable.
A statement read:-
"While 95 per cent of flights are operating as normal, we do recognise the impact of today's cancellations. We are doing our best to mitigate the impact of the current situation that has arisen due to a combination of factors including seasonality, pilots' end-of-year leave, Easter holidays, base restructuring and the shortage of pilots across the industry that Flybe has highlighted over recent months.
"We have already identified several mitigation actions and will issue updates throughout the day. All customers affected have been emailed and advised they can re-book for travel on an alternative flight or apply for a refund."
Flybe's 7am departure from Leeds Bradford to Southampton went ahead as planned and the airline's flights from LBA to Belfast City (14.05), Dusseldorf (15.05), Southampton (17.00), Belfast City (17.15 AND 20.05) are still operating.
On Monday Flybe marked the start of its summer timetable by cancelling the first scheduled flight of the season from Newquay to London Heathrow - a brand-new route. Passengers were instead offered a six-hour coach journey from Cornwall to the capital after their plane was grounded over a technical issue.
Flybe fly to Belfast City, Southampton, Dusseldorf and Newquay from Leeds Bradford, and are introducing a seasonal charter service to Innsbruck this June. The Austrian Alps destination has an airport with one of the most difficult approaches in the world, and pilots must have special training to land there