The Britain-based Syrian Observatory for Human Rights said the raids were carried out by US-led coalition warplanes.
A spokesman for the US-led coalition fighting ISIS told Reuters that its forces had conducted strikes near al-Mayadin on May 25 and 26 and were assessing the results.
The Observatory said more than 40 children were among those killed in the strikes, which levelled al-Mayadin's municipality building.
Many of the families had fled from Raqqa, ISIS's stronghold to the northwest, which US-backed Syrian Kurdish and Arab fighters are pushing towards in an offensive against the jihadists, the Observatory said.
Residents saw reconnaissance aircraft and warplanes circling the city at 7:25 pm (1625 GMT) before they fired missiles which struck two buildings, one of which was a four-storey block housing Syrian and Moroccan families of ISIS fighters.
More strikes took place after midnight.
ISIS is losing ground in both Syria and Iraq under assault from an array of sometimes rival forces in both countries. Many of its fighters who have retreated from other fronts are massing in Syria's Euphrates basin area.
The US-led coalition says it is careful to avoid civilian casualties in air strikes and investigates any that are reported to have taken place.
(Reporting by Angus McDowall and John Davison; Editing by Alison Williams)