Czech police said shortly after 3pm local time that they were responding to the shooting at Charles University's faculty of arts building in Jan Palach Square, before reporting the shooter had been "eliminated".
The Prague emergency services department said on social platform X that 11 people had been killed including the gunman and 11 were seriously wounded.
Petr Nedoma, director of the Rudolfinum Gallery at a concert hall across Palach Square, told Czech TV he saw the shooter.
"I saw a young person on the gallery who had some weapon in his hand, like and automatic weapon, and shooting toward the Manes Bridge," he said.
"Repeatedly, with some interruptions, then I saw as he shot, put hands up and threw the weapon down on the street, it lay there on the pedestrian crossing."
Police sealed off the square and the area adjacent to the building, located in a busy part of town that has a popular street leading tourists to Old Town Square.
Czech TV live broadcast showed several ambulances and police cars with flashing lights lined up alongside the building accompanied by the sound of sirens.
One witness told news website iDnes.cz that they got off at the tram stop by the school and "suddenly I heard shooting".
Klara, a student, told the news website she was among those who police evacuated from the building.
"It was terribly scary, there were a lot of policemen everywhere, who were shouting at us with submachine guns, telling us to run outside," she said.
An email sent to staff and students had said the shooter was in one of the buildings.
"Don't go anywhere, if you're in the offices, lock them and place furniture in front of the door, turn off the lights," the email said.
One X user posted a photo of a group of students, hiding crouched on a ledge of the building.
Prime Minister Petr Fiala cancelled his trip to the east of the country and was en route to Prague, he said on X.
Gun crime is relatively rare in the Czech Republic. In December 2019, a 42-year-old gunman killed six people at a hospital waiting room in the eastern Czech city of Ostrava before fleeing and fatally shooting himself, police said.
In 2015, a man fatally shot eight people and then killed himself at a restaurant in Uhersky Brod.Â
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