Local media said the the shooting took place at the Cameo Night Club.
Cincinnati Police Sergeant Eric Franz told CNN several people are undergoing surgery after the gun attack.
He said police did not have any suspects in custody but were interviewing witnesses.
Sgt Franz said he believed "multiple shooters" were involved.
He said the motive was still unclear but added there was no reason to suspect terrorism.
Cincinnati police at the scene of the Cameo Night Club shooting
Police sealed off the area around the nightclub as the hunt for the gunman continued
We are in the middle of a very horrific situation that occurred at the nightclub with multiple victims
Assistant Police Chief Paul Neudigate
He said the nightclub hires police officers for extra security.
Two officers were stationed at the club's entrance and another two in the car park.
Assistant Police Chief Paul Neudigate said several victims had suffered life-threatening injuries.
He said: ”We are in the middle of a very horrific situation that occurred at the nightclub with multiple victims.
“It's going to be a long night for our homicide units to investigate."
Cincinnati's Cameo Night Club where a gunman opened fire killing at least one reveller
He described it as a "chaotic crime scene" and said police were looking for witnesses, many of whom scattered when the shooting started.
He said:” ”Many of the witnesses fled, but everyone that we can identify is being interviewed.”
Police Captain Kimberly Williams said the gunmen were still at large and the force did not have good descriptions of them.
She said: ”At this point it's unclear exactly what instigated the shooting.
"We believe that there were at least a couple of shooters involved."
Police raced the scene of the Cincinnati nightclub shooting
The shooting happened at about 1am local time while hundreds of people were in the venue and sparked "chaos”.
Capt Williams said: “The Cameo Night Club has had problems in the past but this is by far the worst.”
The shooting comes less than a year after gunman Omar Mateen opened fire at a gay nightclub in Orlando, Florida.
Mateen killed 49 people in the deadliest mass shooting in US history.