Several blasts were heard from the Al-Tanf base used by the US-led coalition near Syria's borders with Iraq and Jordan, a war monitor reported on Wednesday.
"Explosions resounded from the al-Tanf base used by the US-led coalition" fighting the Daesh group, the Britain-based Syrian Observatory for Human Rights said.
According to the monitor, a "drone attack" was responsible for the blasts.
There were no immediate reports of casualties, it reported.
A US official confirmed to AFP that an attack had taken place at the Al Tanf base.
"We know of no casualties," the official said on condition of anonymity.
The Al Tanf base, a desert garrison in southern Syria, was set up in 2016 as part of the fight against the Daesh group.
Damascus and its allies have repeatedly said US troops had no reason to be there.
Iran-backed forces are deployed in close proximity to the desert outpost, which sits on the strategically significant Baghdad-Damascus highway.