It was the third straight day of attacks on the center of the capital, among the deepest and fiercest on the heart of Bashar Assad's seat of power during the civil war.
The car bombing was the deadliest attack inside Damascus in nine months and within hours, two other bombings and a mortar attack on the military compound followed.
While no one group has claimed responsibility, the attacks suggest that rebel fighters who have gotten bogged down in their attempts to storm the capital are resorting to guerrilla tactics to loosen Assad's grip on the capital.
The day's deadliest attack struck a main street on the edge of central Mazraa neighborhood, near the headquarters of Assad's Baath party and the Russian Embassy, as well as a mosque, a hospital and a school.
TV footage of the blast site showed firemen dousing a flaming car with hoses. The state news service, SANA, published photos showing a large crater in the middle of the rubble-strewn street and charred cars.
Witnesses at the scene said a car exploded at a security checkpoint between the Russian Embassy and the central headquarters of Assad's ruling party.
"It was huge. Everything in the shop turned upside down," one local resident said. He said three of his employees were injured by flying glass that killed a young girl who was walking by when the blast hit.
"I pulled her inside the shop but she was almost gone. We couldn't save her," he said, speaking on condition of anonymity for fear of retribution for speaking with foreign media.
Ambulances rushed to the scene of the blast, which shattered windows and sent up a huge cloud of smoke visible throughout much of the city, witnesses said.
State TV called it a "terrorist" attack by a suicide bomber. It said at least 53 people were killed and more than 200 wounded.
The Britain-based activist group the Syrian Observatory for Human Rights said at least 42 people were killed, most of them civilians. Some members of the Syrian security forces were also killed, it said.
There was no way to immediately reconcile the differing death tolls.
The bombing appeared to be the second most deadly in the Syrian capital since the uprising against Assad began 23 months ago. Fifty-five people were killed in the first, a double suicide bombing outside of an intelligence building in May, 2012.
The most extreme of Syria's rebel groups, Jabhat al-Nusra, claimed responsibility for that and other bombings that have struck targets associated with the regime but also killed civilians.
Such tactics have galvanized Assad's supporters and made many other Syrians distrustful of the rebel movement as a whole, most of whose fighting groups do not use such tactics.
There was no immediate claim of responsibility for Thursday's attack.
An official at his office, about 500 yards from the site of the explosion, said Hawatmeh was wounded in the hands and face from flying glass. He was taken to hospital and later released.
In a separate attack, Syrian state TV said mortar shells exploded near the Syrian Army General Command in central Damascus, causing no casualties. The station said the building was empty because it was under renovation.
The Britain-based activist group Syrian Observatory for Human Rights said two mortar rounds struck near the building but did not report casualties.
On Wednesday, two mortar shells exploded next to a soccer stadium in Damascus, killing one player. The day before, two mortar shells blew up near one of Assad's three palaces in the city, causing only material damage.
Between the car bomb and the mortar attack near the army command, a security official reported another blast in the capital's northeastern Barzeh neighborhood. He had no other information and spoke on condition of anonymity because he was not authorized to brief the media.
The Observatory, which relies on a network of anti-regime activists inside Syria, said two car bombs had exploded near security centers in Barzeh, followed by intense clashes between rebels and security forces.
Syrian state media also reported that security forces in Damascus had arrested a second, would-be suicide bomber driving a car full of explosives near the site of the Mazraa bombing.
Damascus has so far mostly avoided the large-scale violence that has destroyed other Syrian cities, though deadly car bombings have targeted government buildings in the capital.
In May 2012, twin car bombs exploded outside a military intelligence building, killing 55 people in the deadliest attack against a regime target in the capital since the uprising began 23 months ago.
And in July, rebels detonated explosives inside a high-level crisis meeting in Damascus that killed four top regime officials, including Assad's brother-in-law and the defense minister.
Following that attack, rebel groups who have established footholds in suburbs of the capital pushed in, clashing with government forces for more than a week before being routed and pushed out.
Since then, government jets have heavily bombed rebel-held suburbs and rebels have managed only small incursions on the city's south and east sides.
In the southern town of Daraa, where Syria's uprising began nearly two years ago, the Observatory said the 18 people killed in the airstrike included eight rebel fighters, three medics, one woman and one young girl.
Syria's conflict began in March 2011 with political protests against the government and has since evolved into a civil war between Assad's regime and hundreds of rebel groups seeking to topple it. The United Nations says some 70,000 people have been killed in the conflict so far.
International diplomacy has failed to slow the fighting.
On Thursday, British Foreign Secretary William Hague said his message to Assad is that "it is time to go."
He said the senseless killing must be brought to an end through a credible political process leading to a transition in Syria.
He also called on Assad to respond to a dialogue offer made recently by Syrian opposition chief Mouaz al-Khatib.
"A political settlement, a political agreement on a transition is the way forward in Syria to bring to an end this terrible and unacceptable loss of life."
Al-Khatib has said he is open to talks with the regime that could pave the way for Assad's departure, but that the Syrian leader must first release tens of thousands of detainees. The government has refused.