The plane, carrying three people, was departing for Honolulu from UPS Worldport at Louisville Muhammad Ali International Airport when it crashed.
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.
At least four people were killed, said airport spokesman Jonathan Biven.
Among the 11 who were hurt, some had "very significant" injuries, Kentucky Governor Andy Beshear said.
"Anybody who has seen the images, the video, knows how violent this crash is," he said.
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.
"We all know somebody who works at UPS," Louisville Metro Council member Betsy Ruhe said. "And they're all texting their friends, their family, trying to make sure everyone is safe.
"Sadly, some of those texts are probably going to go unanswered. My heart goes out to those families and those friends."
UPS acknowledged the crash in a brief statement and said the National Transportation Safety Board would handle the investigation.
The airport, meanwhile, was shut down after the Tuesday afternoon crash and wasn't expected to resume operations until Wednesday morning, US time.
"We don't know how long it's going to take to render that scene safe," said Louisville Police Chief Paul Humphrey.
The governor said a business, Kentucky Petroleum Recycling, appeared to be "hit pretty directly," and a nearby auto parts operation was also affected.
A video taken by Leirim Rodríguez shows several massive balls of flames exploding into the sky in a row, followed by large billowing clouds of black smoke.
Rodriguez told the AP she and her husband just happened to be in the area at the time of the explosion.
The Louisville airport is only a 10-minute drive from the city's downtown, which sits on the Ohio River bordering the Indiana state line. There are residential areas, a water park and museums in the area.
With Reuters
