The attack came as the Kurdish-Arab alliance known as the Syrian Democratic Forces presses an offensive against IS in the town of Tabqa as part of an assault on the jihadist bastion Raqa.
The dawn IS attack hit a makeshift camp where some 300 families were waiting to cross into SDF-held territory in Hasakeh province, in northeastern Syria.
"At least five suicide attackers blew themselves up outside and inside a camp for Iraqi refugees and displaced Syrians in Hasakeh province," said Rami Abdel Rahman, the head of the Syrian Observatory for Human Rights monitoring group.
The makeshift camp lies in the Rajm al-Salibeh area just inside Syrian territory, and at least 21 of the dead were displaced Syrians or Iraqi refugees, the Observatory said.
"At least 30 people were wounded, and the death toll may rise because some people are in critical condition and others are still unaccounted for," the Britain-based monitor said.
Kamal Derbas, a press officer for the Kurdish Red Crescent, put the civilian death toll at 22.
He told AFP the attack began at 4:00 am local time and that 35 people were wounded.
Civilians fleeing IS in both Syria and Iraq have made their way to the desolate border region seeking protection and onward passage to safety in Kurdish-controlled territory.
But conditions in the area are harsh, with little shelter and authorities often overstretched.
IS once controlled large parts of Hasakeh province, but it has been pushed out of almost all of it, with Kurdish authorities now in control of most of the area.
Syria's government maintains a small presence in the province, mostly in its capital Hasakeh city.
Backed by a US-led air coalition, the SDF has waged a months-long campaign against the jihadists across northern Syria and is now closing in on their bastion of Raqa.
In recent days, it has captured most of the key town of Tabqa, which occupies a strategic position on a supply route about 55 kilometres (35 miles) west of Raqa city.
More than 320,000 people have been killed in Syria since the conflict began in March 2011 with anti-government protests.
The group is also on the defensive in neighbouring Iraq, where the army and allied fighters are pushing to recapture the city of Mosul from IS.
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