The US-led international coalition later confirmed the incident in a statement, saying the armed drone was downed "after it displayed hostile intent and advanced on Coalition forces" that "were manning an established combat outpost to the northeast of At Tanf where they are training and advising partner ground forces in the fight against ISIS."
The drone was downed just outside the 55 kilometer de-confliction zone, according to the officials.
It was an Iranian-made Shahed 129 and was thought to be armed and in firing range of US troops.
One official said that the drone was shot down because it was "assessed to be a threat."
The Iranian-made Shahed 129 is the same type that was shot down earlier this month after it dropped a "dud" munition near a patrol being carried out by coalition troops and local forces.
That drone was shot down after it dropped one of several weapons it was carrying near a position where coalition personnel are training and advising partner ground forces in the fight against ISIS.
The incidents mark an escalation in the area around At Tanf -- a base near the Syrian-Jordanian border manned by coalition forces that are advising an anti-ISIS Syrian rebel group.
It also comes just days after a US F/A-18 shot down a regime warplane after it dropped bombs near US-backed Syrian Democratic Forces fighting ISIS in the area around Tabqah, Syria, in the country's north.
That incident prompted the Russian ministry of defense to announce that it would suspend the de-confliction hotline with the coalition which is designed to prevent any accidents in the skies over Syria. The Russian defense ministry's statement added that any coalition aircraft flying west of the Euphrates River would be tracked and "considered air targets."
The row prompted the Australian government to announce that it would "temporarily" halt its airstrikes in Syria
Tuesday's statement from the international coalition stressed that the international effort remained focused on ISIS but said that coalition forces had the right to self-defense.
"The coalition does not seek to fight Syrian regime, Russian, or pro-regime forces partnered with them, but will not hesitate to defend coalition or partner forces from any threat," the statement said, adding that "There is a de-confliction mechanism in place with Russian forces to reduce uncertainty in this highly contested space and mitigate the chances of strategic miscalculation."
But the statement also came with a warning to pro-regime aircraft:
"Given recent events, the coalition will not allow pro-regime aircraft to threaten or approach in close proximity to coalition and partnered forces," it said.