The Syrian Observatory for Human Rights said another three people were also wounded when "an explosion went off inside a car in the city's Al-Gharbi neighbourhood."
Rami Abdel Rahman, the head of the Britain-based Observatory, could not confirm whether the casualties were civilians or combatants.
Syrian state news agency SANA also reported the blast, but gave the death toll as five people.
Qamishli is mostly under the control of Kurdish authorities, though Syrian government forces have a limited presence in the city's "security quarter".
It has been targeted with car bombs on multiple occasions during Syria's seven-year conflict, many of them claimed by Daesh.
But the city had been quiet for months before Sunday's blast.
In September, a motorcycle bomb killed a child and wounded seven people, in an attack that Kurdish security forces blamed on a pro-government militia.
Syria's uprising broke out in March 2011 with protests against the government.
Regime forces withdrew from the country's Kurdish-majority areas in 2012, paving the way for key Kurdish parties to set up a system of self-rule.