The incident began at about 2am (6am GMT) at the Pulse nightclub in the city’s downtown area. Witnesses said a gunman opened fire with an automatic weapon.
"Shooting at Pulse Nightclub on S Orange. Multiple injuries. Stay away f-rom area," Orlando police wrote on Twitter.
The nightclub urged patrons in a post on its Facebook page to “get out” and “keep running". Local media reported that f-rom seven to as many as 20 people had been shot in the attack.
Speaking to Sky News, clubber Ricardo Negron, who was inside when the shooting began, described how the gunman raked the club with bullets.
"At around 2am someone started shooting. People just d-ropped on the floor. I guess the shooter was shooting at the ceiling because you could see all the glass f-rom the lamps falling," he told the network.
He described hearing "non-stop firing" which probably lasted less than a minute but felt like a lot longer.
"There was a brief pause in the shooting and some of us just got up and ran out the back."
"People have definitely been injured -- or worse."
It was not immediately clear how many people were inside the club when the shooting began.
Another clubber called Christopher Hanson told CNN he heard "loud banging noises, like gunshots going off".
He said at first he thought it may have been the music "until you heard too many shots. It was like, bang, bang, bang, bang".
"I didn't see any of the actual shooters. I just saw bodies going down," he told CNN, saying he was ordering a drink at the bar at the time.
"I fell down. I crawled out. People were trying to escape out the back. I just know that when I hit the ground, I was crawling and I hit my elbows and my knees. When I got across the street, there were people -- blood everywhe-re," he said.
The incident came just two days after a deadly shooting at the nearby Plaza Live Theater in which a heavily-armed gunman shot and critically wounded singer Christina Grimmie, a former contestant on the popular TV talent show "The Voice".
She was rushed to hospital but died of her wounds.
(FRANCE 24 with AFP, AP and REUTERS)