JetBlue Airways will launch service between New York's John F Kennedy airport and Cartagena in Colombia from 2 November.
The carrier will operate Airbus A320 aircraft on the route three times a week.
JetBlue already operates to Bogota in Colombia from Orlando and Fort Lauderdale. The Cartagena route will be its third route to Colombia.
"Cartagena is a place we've long had our eye on," says John Checketts, director of route planning for JetBlue, in a statement. "It's one of the most amazing destinations in the Caribbean, a UNESCO World Heritage Site with unparalleled beauty, and a perfect combination of history, beaches, and culture."
The airline will be the only carrier operating non-stop between New York and Cartagena.