A US-led coalition has been carrying out air strikes and ground operations in Syria targeting Islamic State suspects in recent months, often with the involvement of Syria's security forces.
President Donald Trump had vowed to retaliate after a suspected IS attack killed US personnel last weekend in Syria.
Defense Secretary Pete Hegseth said the strikes targeted "ISIS fighters, infrastructure, and weapons sites" and that the operation was "OPERATION HAWKEYE STRIKE".
"This is not the beginning of a war - it is a declaration of vengeance," Hegseth said.
"Today, we hunted and we killed our enemies. Lots of them. And we will continue."
Trump said on social media that the Syrian government fully supported the strikes and that the US was inflicting "very serious retaliation".
At a speech in North Carolina on Friday night, Trump called it a "massive" blow against the ISIS members that the US blames for the December 13 attack on coalition forces.
"We hit the ISIS thugs in Syria. … It was very successful," Trump said at a rally in Rocky Mount, North Carolina.
US Central Command said the strikes hit more than 70 targets across central Syria on Friday, adding that Jordanian fighter jets supported the operation.
One US official said the strikes were carried out by US F-15 and A-10 jets, along with Apache helicopters and HIMARS rocket systems.
Syria reiterated its steadfast commitment to fighting Islamic State and ensuring that it has "no safe havens on Syrian territory", according to a statement by the foreign ministry.
Two US Army soldiers and a civilian interpreter were killed on Saturday in the central Syrian town of Palmyra by an attacker who targeted a convoy of American and Syrian forces before being shot dead, according to the US military.
Three other US soldiers were also wounded in the attack.
About 1000 US troops remain in Syria.
The Syrian interior ministry has described the attacker as a member of the Syrian security forces suspected of sympathising with Islamic State.
Syria's government is led by former rebels who toppled leader Bashar al-Assad last year after a 13-year civil war, and includes members of Syria's former al-Qaeda branch who broke with the group and clashed with Islamic State.
Syria has been co-operating with a US-led coalition against Islamic State, reaching an agreement in November when President Ahmed al-Sharaa visited the White House.
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