The force of the explosion, which police said was believed to have been caused by a gas leak, blew out windows in nearby streets, and shook buildings across the Vltava river in the Czech capital.
Police have sealed off the popular tourist area and evacuated around 220 people from several nearby buildings, Prague police spokesman Tomas Hulan said.
Emergency services chief Zdenek Schwarz told the novinky.cz news website that three or four dead people may be buried in the rubble
of the damaged building, which is near Prague's historic National Theatre.
"The gas company workers haven't allowed rescuers in the building where the blast occurred, but (detection) dogs have marked the place a few times so we suppose there might be three or four dead people there," he said.
An AFP photographer at the scene saw dozens of people with cuts, likely sustained by shattered glass from windows along the debris-covered Divadelni Street. Injured victims were treated on the spot for cuts, some with blood streaming down their faces and bandages on their heads and many of them in shock.
Prague emergency service spokeswoman Jirina Ernestova told AFP that about 40 people had been taken to hospital for treatment.
Schwarz also told Czech TV that four people had suffered serious injuries, while other Czech media said up to 55 may have been hurt.
"A gas blast seems to be the most likely cause. The explosion was rather massive and damaged windows in several streets," Hulan told the television station, adding that several hundred Prague police officers were in action.
Czech media said the blast moved the wall of the building, a former block of flats now used as office space, by five centimetres (two inches) and quoted witnesses as saying they could smell gas in the street.
Prime Minister Petr Necas said in a statement that he was "deeply affected by the tragedy".
The buildings in the area were mostly built in the 19th century, including the ornate National Theatre, whose adjacent modern section was damaged by the blast.
Students and teachers from two nearby universities panicked and ran out when the blast shook their buildings, fearing a terrorist attack, an unnamed student told Czech TV.
"Blast in Divadelni (street), many injured. Windows broken at journalism faculty," Milos Cermak, a Czech journalist who was lecturing in an adjacent university building at the time, wrote on Twitter.
"Police say gas still leaking. Helicopter above us. Classes cancelled for rest of week," he added.
Cermak described the explosion as "a terrible blast."
"We don't know what happened. The firefighters helped some students covered in blood out of the building," Tomas, a student at the faculty, told the website of the Lidove noviny broadsheet.
The Czech capital welcomed more than 5.4 million tourists last year.
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