Ryanair is ending its Derry to London route from next spring.
Summer flights to Faro in Portugal are also being dropped, the City of Derry Airport disclosed.
Stansted services will stop in March next year and Faro in April.
From April 2017 Ryanair will operate five weekly services to Glasgow International and two to Liverpool from City of Derry Airport
Derry City and Strabane District Council's chief executive John Kelpie is seeking a Public Service Obligation (PSO) commitment from the British Government that a direct route be operated between Derry and London.
He said: "We believe our peripheral location where connectivity to London is vital for the development of our regional economy and the social development of our region, will put us in a strong position to secure a PSO."
Key challenges facing the loss-making airport include air passenger duty, the legacy of the global financial crisis and the low-yield environment this has created, competition from Dublin which pays no tax and a reducing pool of airlines which are averse to risk.
Mr Kelpie added: "We are committed to continuing to work proactively over the coming weeks and months to safeguard the airport's future and put in place a strategy that will ensure the airport continues to provide air connectivity for business and tourism, and remains an important regional gateway and the airport of choice for the North West."