Police identified the gunman as area resident Stephen Paddock, 64, but said they had no information yet about his motive.
He was not believed to be connected to any militant group, Clark County Sheriff Joseph Lombardo told reporters.
“Confirming that one suspect is down. This is an active investigation. Again, please do not head down to the Strip at this time,” the Las Vegas Metropolitan Police Department said in a tweet.
The police reported closing off about a mile of Las Vegas Boulevard and asked the public to steer clear of the area.
The dead included one off-duty police officer, while at least one other officer was critically injured, Lombardo said. Police warned the death toll may rise.
Witnesses heard numerous gunshots at the casino hotel, where police tactical teams were searching for the attacker, according to reports on U.S. media outlets.
The Las Vegas hospital said it was taking in several people with gunshot wounds.
Video footage circulating on Twitter purportedly of the Mandalay Bay showed a crowd enjoying a concert before what sounds like volleys of automatic gunfire halt the performance.
The White House says Donald Trump is being briefed about the shooting. He just put out this tweet to express condolences.
“My warmest condolences and sympathies to the victims and families of the terrible Las Vegas shooting. God bless you,” Trump twitted.
The shooting broke out on the last night of the three-day Route 91 Harvest festival, a sold-out event attended by thousands and featuring top acts such as Eric Church, Sam Hunt and Jason Aldean.