A truck packed with explosives first blew up near the Turkish border.
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In May, Kurdish-led Syrian forces, backed by US-led airstrikes, started a major attack to dislodge IS from Minbij and have since gained ground against the radical group.
The death toll was expected to rise due to the number of seriously injured.
The blast was the biggest and deadliest to hit Qamishli, close to the border with Turkey, since the Syrian conflict began in March 2011 with anti-government protests before spiralling into a bloody, multi-front war.
The commander of the Kurdish security forces, Joan Ibrahim, vowed to avenge the “dirty” attack, which he said came in retaliation for the siege imposed by the SDF on Manbij. Two people were slightly hurt in Nusaybin, said one witness.
The terror group has claimed responsibility for a spate of terror attacks recently, including one that killed at least 21 people this week in Baghdad.
It showed footage from the scene of the blast, with smoke rising from buildings and rubble from the blasts. And in July an Islamic State suicide bomb killed at least 16 people in Hasaka.
Islamic State claimed responsibility for the attack.
Local officials said hospitals in the city had been swamped with casualties.
The attacks comes as fighting intensifies between the YPG and the extremist organization, with the former capturing large areas of territory from the Islamic State group in northeastern Syria.
The city of Qamishli, which lies just across the border from the Turkish province of Mardin, has seen relatively little violence compared to other parts of Syria.
Abdel Rahman told dpa earlier a auto bomb targeted the Justice Department and Kurdish internal security force in the town, which is located in al-Hasaka province.
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There’s also a significant presence of the Kurdish-U.S backed democratic forces that are fighting on the northern side of the country against the Islamic State.
