Syrian state media gave a toll of 44 dead and 140 injured in the bomb attack, which hit a western district of the city where several local Kurdish ministries are located.
The attack was carried out by a suicide bomber who blew himself up inside a truck, Kurdish officials told AFP.
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 blast was initially described as a double bombing, but local officials and the Syrian Observatory for Human Rights monitor said the bomb had also detonated a nearby fuel container, leading to reports of a second explosion.
An AFP journalist saw devastating scenes in the bomb’s aftermath, with distraught civilians, some covered in blood, staggering through rubble past twisted metal and the burned-out remains of cars.
One man running along the streets was completely covered in blood, his shirt drenched red.
He was gripping the arm of a small boy whose face was grey and red with blood and dust.
They ran past a hysterical woman who was crying and screaming, her clothes torn. A girl and boy stood next to her, apparently in shock.
Children could be heard screaming as smoke rose from small fires that continued to burn amongst the rubble.
Civilians and local security forces with guns slung across their backs worked to carry the dead and wounded from the remains of damaged and destroyed buildings.
Qamishli has regularly been targeted in bomb attacks, many of which have been claimed by the Islamic State group.
The IS-linked Amaq agency reported that a suicide truck bomber hit Kurdish forces in Qamishli, without explicitly claiming the attack as an IS operation.
An AFP reporter in the city said a suicide bomber blew himself up by a checkpoint near local Kurdish adminstration buildings including the defence ministry.
A source in the Kurdish Asayesh security forces told AFP “this is the largest explosions the city has even seen.”
Observatory head Rami Abdel Rahman said the area struck by the bomb was considered a secure zone, with multiple checkpoints and security measures in place.
“This blast is the biggest in Qamishli in terms of both the toll and the damage since the beginning of the war,” he said.
Local officials said hospitals in the city had been swamped with casualties from the attack.
And Syrian state television carried an appeal from the governor of Hasakeh province, where Qamishli is located, urging residents of the city to “go to public and private hospitals to donate blood for the victims of the terrorist bombings.”
Qamishli is under the shared control of the Syrian regime and Kurdish authorities, who have declared zones of “autonomous administration” across parts of north and northeast Syria.
The Kurdish People’s Protection Units (YPG) have been a key force fighting IS in north and northeastern Syria.
They are the main component in the Syrian Democratic Forces alliance that is currently battling IS in the town of Manbij, with air support from the US-led anti-IS coalition.
More than 280,000 people have been killed in Syria since the war began, with over half the population displaced.