A Boeing 737 plane crashed shortly after taking off from Havana's main airport, Cuban state-run media reported.
There was no immediate word on casualties.
The plane was a domestic flight going to Holguin, carrying 104 passengers, state-run TV said.
Officials said the plane was headed to the eastern city of Holguin when it crashed between the airport in southern Havana and the nearby town of Santiago de las Vegas.
Images on TV and social media showed a large plume of black smoke above the airport.
Ambulances and firefighters were rushing to the scene.