The blast that ripped away large sections of the outer wall at the Hotel Saratoga, a 19th century structure in Old Havana, apparently was due to a gas leak, according to the Twitter account of the office of President Miguel Díaz-Canel, who went to the site.
It said at least eight people had been killed and that search and rescue efforts were underway for people possible trapped.
Photos showed much of the hotel's outer wall blown away, exposing interior rooms, with clouds of dust billowing into the sky.
VIDEO: Apparent gas leak causes blast that damages Havana hotel; 8 deaths reported
A school next door had been evacuated.
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Police cordoned off the area as firefighters and ambulance crews worked inside.
Photographer Michel Figueroa said he had been walking past the hotel when "the explosion threw me to the ground, and my head still hurts.... Everything was very fast."
Yazira de la Caridad, mother of two, said the explosion shook her home a block from the hotel: "The whole building moved. I thought it was an earthquake," she said. "I've still got my heart in my hand."
Mayiee Pérez said she had rushed to the scene after receiving a call from her husband, Daniel Serra, who works at a foreign exchange shop inside the hotel. She said he told her, "I am fine, I am fine. They got us out," but had been unable to reach him since.
The five-star, 96-room hotel in Old Havana has two bars, two restaurants and a rooftop pool, according to its website.