Washington has frozen all US assets held by Syria's military intelligence chief, accusing him of contributing to violence in Lebanon and Iraq.
Syria is under pressure to stop militants using its border with Iraq
Asef Shawkat, brother-in-law of President Bashar al-Assad, is said by the US to have promoted terrorism and interference in Lebanese affairs.
He is also accused by Washington of playing a direct role in Syria's alleged support for militants in Iraq.
There was no immediate response from Mr Shawkat to the US decision.
It is the latest US action apparently aimed at increasing pressure on the Syrian government.
Damascus has been under heavy international pressure since the assassination of former Lebanese Prime Minister Rafik Hariri in Beirut on 14 February last year when Syrian forces were still stationed in the country.
The attack led to widespread protests in Lebanon and extensive international pressure on Syria, forcing it to end its 29-year-old military presence in Lebanon in April.
In June, the treasury department froze the assets of Syria's late Interior Minister, Ghazi Kanaan, and its chief of military intelligence for Lebanon, Rustum Ghazali.
On Wednesday, the department ordered US banks to block any assets found in the US belonging to Mr Shawkat and banned American citizens from doing business with him.
He had, it said, played a role in furthering Syria's "support for terrorism and interference in the sovereignty of Lebanon".
It accused Mr Shawkat of having dealings with Lebanese and Palestinian militant groups designated by the US as terrorists.
White House spokesman Scott McClellan said Mr Shawkat had "directly contributed to Syria's support for terrorism, including the insurgency in Iraq".
"Today's action is a significant signal that those like Mr Shawkat who support Syrian terrorism will be held to account," he added.
Syria is on the US government's list of countries and organisations accused of supporting terrorism, although the two sides maintain diplomatic relations.