April Odom, the Director of Communications for Birmingham Mayor William Bell confirmed to ABC News that both the pilot and co-pilot of the plane were killed in the crash. The names of the crew were not immediately released.
Flight 1354, which was en route from Louisville, Ky., was on final approach to Birmingham-Shuttlesworth International when it went down at about 5 a.m. CT, authorities say.
The Transportation Security Administration said they believe the pilot and co-pilot were the only individuals on board with the cargo.
Federal Aviation Administration officials say the plane crashed about a half-mile off the airport property. Toni Herrera-Bast, a spokeswoman for the Birmingham-Shuttlesworth International Airport, said the jet crashed in an open field just outside the airport. The plane then broke into several pieces and caught fire. There are no homes in the immediate area of the crash.
It's unclear what caused the crash. The National Transportation Safety Board is launching an investigation into the incident.
Mayor Bell, who was briefed by the city's fire chief, said there were two or three small explosions that authorities believe were from aviation fuel.
People living near the airfield reported seeing flames coming from the plane and hearing its engines struggle in the final moments before impact.
"It was on fire before it hit," said Jerome Sanders, who lives directly across from the runway.
Weather conditions at the time were rainy with low clouds.
UPS released a statement following the crash:
"At this time, we are still determining the details of the incident. We will release more information as it becomes available. As we work through this difficult situation, we ask for your patience, and that you keep those involved in your thoughts and prayers."
It was not immediately known what the plane was carrying; UPS spokesman Jeff Wafford said only that the plane was carrying a variety of cargo.
The plane was built in 2003 and had logged about 11,000 flight hours over 6,800 flights, Airbus said in a news release.
The A300, Airbus' first plane, began flying in 1972. Airbus quit building them in 2007 after making a total of 816 A300 and A310s. The model was retired from U.S. passenger service in 2009.
Wednesday's crash comes nearly three years after a UPS cargo plane crashed in the United Arab Emirates, just outside Dubai, killing both pilots.
Authorities there blamed the Sept. 3, 2010, crash on the jet's load of 80,000 to 90,000 lithium batteries, which are sensitive to temperature. Investigators determined that a fire probably began in the cargo containing the batteries.
The Associated Press and ABC News contributed to this report.