Police said in a Twitter message that there were "multiple injuries". Local media reported that from seven to as many as 20 people had been shot at the Pulse nightclub, but had no further details.
The nightclub urged patrons to "get out" and "keep running" in a post on its Facebook page.
Several patrons had posted on social media that a gunman was holed up inside and holding hostages. One man who said he was inside the club posted that the shooting broke out around 2 a.m. and that he heard about 40 shots being fired.
Police said they had carried out a "controlled explosion" at the club hours after the shooting broke out, but did not say why that was done. They described the scene as a "fluid situation".
Video posted online showed a large number of police and emergency vehicles outside the nightclub. Bomb sniffing dogs were also on the scene, CNN reported.
The nightclub shooting occurred just a day after a man thought to be a deranged fan fatally shot Christina Grimmie, a rising singing star who gained fame on YouTube and as a contestant on "The Voice", while she was signing autographs after a concert in Orlando.