The US Federal Aviation Administration (FAA) said the McDonnell Douglas MD-11 departing for Hawaii crashed at around 5.15pm local time (2215 GMT).
In a statement, UPS said three crew members were on board, adding “we have not confirmed any injuries/casualties.”
Louisville mayor Craig Greenberg reported there were “multiple injuries” and that the plane was carrying a large amount of fuel.
The cause of the crash was under investigation by the FAA and the US National Transportation Safety Board (NTSB).
Video shared by local broadcaster WLKY appears to show the aircraft’s left engine on fire as it tried to lift off.
Louisville serves as the main US air hub for UPS, according to a company fact sheet.
The package delivery giant travels to more than 200 countries via nearly 2,000 flights per day, with a fleet of 516 aircraft. UPS owns 294 of those planes and hires the rest through short-term leases or charters.
Aerial footage of the crash site showed a long trail of debris as firefighters blasted water on the flames, with smoke billowing from the disaster area.
Government shutdown
The crash comes amid one of the longest government shutdowns in US history, with transportation secretary Sean Duffy warning of “mass chaos” earlier Tuesday due to a lack of air traffic control staff.
“You’ll see mass cancellations, and you may see us close certain parts of the airspace, because we just cannot manage it because we don’t have the air traffic controllers,” Duffy told reporters.
In a statement on X, Duffy called footage of the crash “heartbreaking,” adding: “Please join me in prayer for the Louisville community and flight crew impacted by this horrific crash.”
In January, an American Eagle airliner hit a military Black Hawk outside Washington’s Ronald Reagan airport, killing 67 people.
That crash, which ended the United States’ 16-year streak of no fatal commercial air crashes, has added to concerns about the US air traffic control system, which some regard as an understaffed operation beset by problems with old equipment.