After ending its combat mission in 2014, the US military still uses airstrikes by drones and other aircraft in Afghanistan to target suspected members of al-Qaeda and Daesh (ISIL) and back up Afghan forces battling a Taliban insurgency.
There were no injuries or civilian damage in the crash of the state-of-the-art US$14-million MQ-9 Reaper late on Saturday night, Captain Bryan Bouchard of the 455th Air Expeditionary Wing said in a statement.
"The crash was contained on Kandahar airfield," he added. "US Air Force authorities will investigate the cause of the crash but hostile fire was not a factor."
Usually guided remotely by pilots outside Afghanistan, unmanned aircraft have played a major, and sometimes controversial, role in the American war, acting as spy planes and launching missiles at suspected militants.
In November, another Reaper operating out of Kandahar and armed with missiles was totally destroyed when it went down more than 483 km (300 miles) to the northeast of the base in a mountainous area.
The cause of that crash was not made public but the military also ruled out ground fire as a suspected factor, Reuters reported.
Reapers were the US Air Force's first specifically designed "hunter-killer" unmanned aircraft, and are larger and more powerful than the older MQ-1 Predator drones.