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7 year oldThe drone was thought to be armed and threatening US troops on the ground, officials said.
It was shot down near Tanf, an outpost of the US-led coalition.
This is the latest incident in the skies over Syria, after the US shot down a Syrian fighter plane on Sunday and another drone earlier this month.
The F-15 plane downed the drone around 00:30 on Tuesday (21:30 GMT Monday) north-east of Tanf, according to a US military statement.
The shooting down underscores the growing tensions in the region as a battle develops for the control of eastern Syria, BBC Defence and Diplomatic Correspondent Jonathan Marcus says.
Military officials who spoke to CNN described it as a Shahed 129, a model unveiled by Iran in 2012.
It is said by the Iranians to have a range of 2,000km (1,240 miles) and capable of carrying bombs and missiles.
"They were threatening our forces on the ground," the US official quoted by AFP said. "Their course was on a run toward our folks to drop a munitions on them."
The last drone the US says it shot down was also reportedly destroyed near Tanf after firing on coalition forces.
Tanf has been used by Western special forces as well as Syrian rebel forces.
In Syria's complex civil war, the US backs some rebel groups opposed to President Assad, as well as fighters seeking to drive out the Islamic State (IS) group.
Syrian government forces and pro-government militias, supported by Russia and Iran, are fighting both rebel groups and IS.
Last month, US-led coalition aircraft bombed a convoy of pro-Syrian government forces near Tanf.
The Syrian plane destroyed on Sunday, a Su-22 fighter bomber, was hit after reportedly dropping bombs near the town of Tabqa in Raqqa province.
As well as announcing that US-led coalition warplanes would be tracked, Russia's ministry of defence suspended a hotline set up to avoid clashes between US and Russian aircraft over Syria.