The Airbus A300 plane, which took off from Louisville in Kentucky, crashed at around 6 a.m. local time (1000 GMT) while approaching the airport in Birmingham, said the Federal Aviation Administration.
Birmingham Mayor William Bell confirmed the pilot and co-pilot, who had not been identified immediately, were killed in the tragedy, but no more casualties were reported so far.
The U.S. National Transportation Safety Board said it had sent a response team to the site of the crash.
UPS said in a statement that the company was still determining the details of the incident.
The crash caused at least two explosions and strewed debris across a long path, NBC News affiliate WVTM reported.