"The toll includes 33 children. They were families seeking refuge in the town's municipal building," said Rami Abdel Rahman, head of the Syrian Observatory for Human Rights.
"This is the highest toll for relatives of IS members in Syria," Abdel Rahman told AFP.
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UN human rights chief Zeid Ra'ad Al Hussein said "all states" whose air forces are active in the anti-IS missions needed "to take much greater care to distinguish between legitimate military targets and civilians."
The Britain-based Observatory gathered information from civilian and medical sources on the ground in IS-held Mayadeen, which was facing its third day of the fierce bombing.
According to the Observatory, 37 civilians were killed in coalition raids on the town on Thursday night, including 13 children, and another 15 had been killed in coalition strikes on Wednesday.
The 68-member coalition began bombing IS targets in Iraq in the summer of 2014, and expanded their operations to Syria on September 23 of that year.
This week, the Observatory reported the highest monthly civilian death toll for the coalition's operations in Syria.
Between April 23 and May 23 of this year, coalition strikes killed a total of 225 civilians in Syria, including dozens of children.
The US-led alliance is backing twin ground offensives against IS's last main bastion cities: Raqa in northern Syria and Mosul in neighbouring Iraq.
Yesterday, a Pentagon investigation concluded that at least 105 civilians died in an anti-jihadist air strike on an IS weapons cache in Mosul in March.
Prior to the new revelation, the US military had said coalition air strikes in Iraq and Syria had "unintentionally" killed a total of 352 civilians since 2014.
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