The pilots were on a routine training mission when their jet went down just before 7 p.m. in a desert area just west of the airfield, officials at the base said.
Both pilots were unhurt, the Air Force said, after initially reporting they had minor injuries. Their names weren't immediately released.
The jet, part of the 309th Fighter Squadron, crashed in a field adjacent to the base and there was no damage to property, the Air Force said in a statement.
There was no immediate word on what might have caused the crash, Sgt. Linda Rainey said.
Police and fire departments from Luke and surrounding communities responded.
"An incident like this highlights the close cooperation between our Fire and Emergency Services and their counterparts in the surrounding community," said Brig. Gen. Michael Rothstein, 56th Fighter Wing commander.
Witnesses said they heard the jet's engine sputtering and popping just before the plane went down. Video from a TV helicopter showed plumes of smoke rising from the crash scene.
Luke Air Force Base, about 15 miles west of Phoenix, is the world's largest F-16 training base.
In March 1999, the Air Force temporarily suspended all F-16 fighter flights at Luke after one of the jets crashed in the desert. At the time, it was the fifth such accident at Luke since October 1998.
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