The plane caught fire, sending a column of thick smoke into the sky as fire trucks and other emergency vehicles rushed to the scene.
Birmingham Fire Chief Ivor Brooks said the pilot and the co-pilot, the only two people aboard the aircraft, were killed. He said both were pronounced dead at the scene of the crash.
No other casualties have been reported.
The Federal Aviation Administration said the A300 plane – en route from Louisville, Kentucky, to Birmingham – crashed on approach to Birmingham-Shuttlesworth International Airport at around 5am local time.
The plane went down in an open field that is just outside the perimeter fence of the airport.
Birmingham Mayor William Bell said: “The plane is in several sections.
“There were two to three small explosions, but we think that was related to the aviation fuel.”
The plane appears to have struck a massive hardwood tree north of the runway, and the AP news agency said conditions in the area were rainy with low clouds in the early morning.
Local news reports say homes and a church were close to the crash site.
The news web site al.com quoted a resident of the area, Eddie Smith, as saying he had heard a loud explosion before dawn.
“It shook my house so hard I jumped up,” Mr Smith said, adding he later heard another loud explosion.
The crash has not affected airport operations, a spokeswoman says.