The swathe of territory controlled by IS on either side of the Euphrates River has long been a key target for Washington as it is seen as the main entry point for foreign fighters.
The Pentagon has deployed more than 200 special forces troops alongside the Syrian Democratic Forces (SDF), a Kurdish-led alliance in which it has been trying to boost the Arab element.
US-led coalition aircraft carried out intense strikes on the IS-held town of Manbij, 30 kilometres (20 miles) west of the Euphrates, in support of the offensive, the Syrian Observatory for Human Rights said.
The Britain-based monitoring group, which relies on reports from medics and activists on the ground, said three children were among 15 civilians killed in the pre-dawn raids.
"The campaign for Manbij began on Tuesday," Observatory chief Rami Abdel Rahman told AFP.
"Over the past 24 hours, the SDF have seized control of nine villages... west of the Euphrates," he said.
The advance has brought SDF forces within 18 kilometres (11 miles) of Manbij.
Signup to our newsletter and follow us on Facebook and Twitter!
SDF military adviser Nasser Haj Mansour told AFP that the alliance's fighters were heading from the Tishreen Dam on the Euphrates towards Manbij.
"The clashes are fierce and intense," he said.
The offensive is one of two the SDF has launched against IS in northern Syria in recent weeks.
Last month, the alliance launched an assault on the jihadists north of their de facto Syria capital Raqa, seizing dozens of villages in the north of Raqa province.
Washington sees the SDF -- which is dominated by the Kurdish People's Protection Units (YPG) -- as the most effective ground force against IS in Syria.
With the help of coalition air strikes, the SDF has cleared IS jihadists from large parts of Syria's northeast.
But the US support for the Kurdish-led alliance has angered NATO ally Turkey.
Ankara regards the YPG as a branch of the rebel Kurdistan Worker's Party (PKK), which has fought a three decade insurgency against the Turkish state.