Seventeen children were among 36 IS family members killed in Abu Husn village of Deir Ezzor province near the Iraqi border, the Syrian Observatory for Human Rights said.
Another seven victims had not yet been identified as either civilians or IS fighters, it said.
The US-led coalition has been backing a Kurdish-Arab alliance called the Syrian Democratic Forces (SDF) fighting to expel the jihadists from the pocket around Abu Husn.
"It's the highest death toll in coalition air strikes since the SDF launched its attack against the IS pocket" in September, Observatory chief Rami Abdel Rahman said.
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The coalition has repeatedly said it does its utmost to prevent civilian casualties.
"The avoidance of civilian casualties is our highest priority when conducting strikes against legitimate military targets with precision munitions," spokesman Sean Ryan told AFP this week.
IS overran large swathes of Syria and neighbouring Iraq in 2014, proclaiming a "caliphate" in land it controlled.
But the jihadist group has since lost most of it to various offensives in both countries.
In Syria, the group has seen its presence reduced to parts of the vast Badia desert and the pocket in Deir Ezzor.
The coalition has since 2014 acknowledged direct responsibility for over 1,100 civilian deaths in Syria and Iraq, but rights groups put the number killed much higher.
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