The Trump administration is banning flights from the US to all destinations in Cuba except for Havana.
The move will see the end of JetBlue flights to Santa Clara, Holguin, and Camaguey.
JetBlue will start scrapping the flights in December, the state department said.
The decision also means American Airlines will end flights to Camaguey, Holguin, Santiago, Varadero and Santa Clara flights.
Secretary of State Mike Pompeo tweeted the move would ‘prevent the Castro regime from profiting from US air travel and using the revenues to repress the Cuban people’.
Opponents say it only makes it more difficult for Cuban-Americans to visit family living in regional cities across Cuba.