Assef Shawkat and defence chief Daoud Rajha were killed in a bomb carried by a bodyguard employed by President Assad's inner circle, it was reported by Hezbollah's al-Manar television and a security source in Syria.
The attack on a security building in the capital came amid reports that at least 60 soldiers have been killed in the city in the last 48 hours.
The violence comes ahead of a vote on a new Syrian resolution this afternoon.
Columns of black smoke rose over the Syrian capital after clashes between President Bashar al-Assad's troops and the Free Syrian Army.
The fighting, with tanks and helicopter gunships, raged amid reports that two Syrian brigadier generals crossed into Turkey overnight.A girl wounded by shelling in Homs is treated in hospital
That brings to 18 the number of generals who have fled into Turkey since the conflict began in March last year.
The Britain-based Syrian Observatory for Human Rights said between 40 and 50 government soldiers were killed on Monday in Damascus and at least 20 more yesterday.
Rebels have announced a full-scale offensive in the capital dubbed the "Damascus volcano and earthquakes of Syria". They say the drive to "liberate" the capital has begun.
The Observatory said at least 93 people were killed nationwide on Tuesday - among them 48 civilians.
In Homs province, heavy weaponry was used to pound Tal Kalakh and several district of Homs city itself, injuring many people, including several children, activists said.
Meanwhile, Russia remained at loggerheads with the US and its European allies ahead of a scheduled vote this afternoon on a new Syria resolution.
There appeared to be little hope that the UN's most powerful body would unite behind a peace plan to end the 17-month civil war.
The key stumbling block is the Western demand for a resolution threatening non-military sanctions and tied to Chapter 7 of the United Nations Charter.
That would eventually allow the use of force to end the conflict in Syria. Russia is adamantly opposed to any mention of sanctions or Chapter 7.
International envoy Kofi Annan has been in Russia for two days of high-level meetings, including talks with President Vladimir Putin on Tuesday.
Russia and China have incurred international criticism by twice vetoing UN resolutions to increase pressure on Assad.
British Foreign Secretary William Hague insisted during a trip to Jordan on Tuesday that a Chapter 7 resolution is required to implement Mr Annan's peace plan.
In Beijing, UN Secretary-General Ban Ki-moon sat down for talks this morning with Chinese President Hu Jintao.
After the meeting, Ban said the Chinese leaders shared his view that the situation in Syria is "very serious."
Syrian Rebels 'Down Helicopter In Damascus'