The shooting sent people scrambling across the city's Fountain Square amid cries of "shooter!"
It happened at a 30-story building, home to the corporate headquarters for regional banker Fifth Third Bancorp and other businesses, including popular ice cream, pastry and sandwich shops. The bank building was locked down for most of the morning, and surrounding streets and sidewalks were closed off.
Police Chief Eliot Isaac said the shooter opened fire at about 9:10 a.m. EDT at the loading dock of the Fifth Third Bank building. Isaac said the gunman then entered the bank's lobby where he exchanged gunfire with police. It's unclear if the gunman shot himself or was shot by officers.
Michael Richardson, who works in the bank building, told The Cincinnati Enquirer that he was standing outside the entrance when he heard gunshots in the lobby.
"I looked behind me and saw the guy — he shot and then he shot again. After that I started running."
The gunman wasn't identified immediately, and police didn't comment on possible motive.
"So, a very horrific situation," Isaac said. "We're in the very early stages (of investigation)."
Federal agents were on the scene as police searched through the building.
One of the victims died at the scene. Two more died at University of Cincinnati Medical Center. UC Health spokeswoman Kelly Martin said one victim remained there in critical condition and another was listed as serious. All four received at the hospital had gunshot wounds, she said.
Cincinnati Mayor John Cranley said the gunman was "actively shooting innocent victims." The Fountain Square often hosts concerts, dancing, food trucks and other events around lunchtime or in the evenings and is neighbored by a hotel, restaurants and retail shops.
"It could have been any one of us," Cranley said.
He praised "the heroism" of police who ended the threat within seconds and the response of other emergency personnel.
"It could have been much, much worse," Cranley said.
Witnesses described a chaotic scene, with people running away in fear and confusion while hearing gunshots.
Leonard Cain told The Cincinnati Enquirer he was going inside the bank when someone alerted him there was shooting. He said a woman, who was wearing headphones, didn't hear the warnings and walked into the bank and was shot.
Fifth Third operates some 1,200 banking centers in 10 states. A spokeswoman said the bank didn't have a comment immediately.