Speaking from the scene on Cuban television, President Miguel Diaz-Canel said the blast at the historic, high-end Hotel Saratoga appeared to have been caused by a gas leak.
Cuba's tourism minister, Juan Carlos Garcia, said no foreigners were killed or injured in the blast, according to initial reports.
The hotel, housed in a more than century-old building, had been closed and only workers were inside at time of the explosion, state-run TV said, citing Roberto Enrique Calzadilla, a representative of the military-run company that operates many of the country's hotels.