US Defense Secretary Leon Panetta warned Syrian President Bashar al-Assad on Sunday that the assault on his own population in Aleppo would be a nail in his coffin.
Fighting raged on the second day of a fierce government offensive, as the United Nations said 200,000 civilians had fled and many were trapped after Assad deployed tanks and attack helicopters to try to dislodge the rebels.
The Syrian opposition says government forces are preparing to carry out "massacres" and is pleading the international community to provide heavy weapons to enable rebels to meet the regime onslaught.
"It's pretty clear that Aleppo is another tragic example of the kind of indiscriminate violence that the Assad regime has committed against its own people," Panetta told reporters on a military plane en route to Tunisia.
"And in many ways, if they continue this kind of tragic attack on their own people in Aleppo, I think ultimately it will be a nail in Assad's coffin," he said.
"He's just assuring that the Assad regime will come to an end by virtue of the kind of violence they're committing against their own people."
According to Panetta, Assad has "lost all legitimacy, and the more violence he engages in, the more he makes the case that the regime is coming to an end."
It's no longer a question of whether the regime will fall, "it's when," he added.
More than 20,000 people have been killed, including 14,000 civilians, since the uprising against Assad's rule erupted in March 2011, according to the British-based Syrian Observatory for Human Rights.
"The United States and the international community have made very clear that this is intolerable, and have brought diplomatic and economic pressure on Syria to stop this kind of violence, to have Assad step down and to transition to a democratic form of government," Panetta said.
Obama, waging a tough domestic battle ahead of the November 6 election, has demanded that Assad stand down and offered logistical support to the opposition, but his administration has ruled out using force.
International efforts to squeeze Assad by isolating his regime and seeking sanctions against his inner circle have been frustrated by Russian and Chinese opposition at the UN Security Council.
Panetta said the United States was paying particular attention to securing Syria's chemical and biological weapon sites, especially by maintaining "close cooperation with countries in the region."
His trip to Tunisia is the first stop of an international tour that will also take him to Egypt, Israel and Jordan.