Those numbers are expected to grow, the governor said. The plane crashed as it was departing for Honolulu from Louisville's Muhammad Ali International Airport, the US Federal Aviation Administration said.
Video showed flames on the plane's left wing and a trail of smoke. The plane then lifted slightly off the ground before crashing and exploding in a huge fireball.
Video also revealed portions of a building's shredded roof next to the end of the runway.
"We believe we have at least three fatalities. I believe that number is going to get larger," Kentucky Governor Andy Beshear said at a press briefing.
"Anybody who has seen the images in the video know how violent this crash is".
The plane had three crew members on board, according to UPS.
The crash has drawn a massive response, including from police and fire agencies, and because of the flames, some responders "have had to shelter behind different things", Beshear said.
"It is still a very dangerous situation with different flammables or potentially explosive materials," Beshear said.
Mayor Craig Greenberg told broadcaster WLKY-TV that fuel on the plane was an "extreme reason for concern in so many different ways".
"There are multiple injuries and the fire is still burning. There are many road closures in the area – please avoid the scene," Greenberg said in a social media post.
UPS's largest package handling facility is in Louisville. The hub employs thousands of workers, has 300 daily flights and sorts more than 400,000 packages an hour.
A shelter-in-place order was extended to all areas north of the airport to the Ohio River after the crash, which occurred at 5.15pm on Tuesday, local time.
The Louisville airport is only a 10-minute drive from the city's downtown, which sits on the river bordering the Indiana state line. There are residential areas, a water park and museums in the area.
The McDonnell Douglas MD-11 airplane owned by UPS was manufactured in 1991.
With Reuters
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