The company, which recently had to cut around 10% of its workforce, said it has sold all of its Gatwick arrival and departure slots to Easyjet for £20 million.
The decision will particularly affect Northern Ireland commuters and travellers connecting to other destinations. Easyjet, which operates out of Belfast International Airport, is unlikely to retain the City link.
A Flybe statement accused Gatwick's owners of trying to squeeze out smaller air carriers with charges and claimed fees had amounted to a 102% rise over the last five years.
"No business can swallow such a massive increase in such a short period of time and it is with real regret and some anger that we have made this decision.
"Flybe fully appreciates the implications this will have not only on Northern Ireland passengers but also on the wider regional economy which has come to rely on the convenient lifeline connections we provide to Gatwick."