The Friday strike on the Euphrates Valley village of Baghouz killed 10 IS fighters as well as the six civilians, the Syrian Observatory for Human Rights said.
There was no immediate comment from the US-led coalition.
Baghouz is part of an enclave of less than 15 square kilometres (less than six square miles) that is all that is left of IS territory in Syria following a gruelling Kurdish-led offensive launched with coalition support last May.
The Britain-based Observatory said the coalition had stepped up its airstrikes against IS since the jihadists killed 19 people, four of them Americans, in a suicide bombing on a restaurant in the flashpoint northern town of Manbij on Wednesday.
"The strikes are continuing, and have intensified since the Manbij attack," Observatory chief Rami Abdel Rahman told AFP.
The US losses were the biggest since Washington deployed troops in Syria in 2014 in support of the Kurdish-led Syrian Democratic Forces.
Previously it had reported just two combat losses in separate incidents.
The Manbij bombing rekindled controversy triggered by President Donald Trump last month with his surprise announcement of a full withdrawal from Syria.
The US president justified the order with the assertion that the jihadists had now been largely defeated" in Syria, a claim that the attack threw into renewed question.
Agencies contributed to this report.
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