"If they continue this kind of tragic attack on their own people in Aleppo, I think it ultimately will be a nail in Assad's own coffin," Panetta told reporters.
"What Assad has been doing to his own people and what he continues to do to his own people makes clear that his regime is coming to an end. It's lost all legitimacy," he added.
This is while Syrian security forces are clearing more areas across the country of militants.
The US official made the remarks ahead of a weeklong trip to the Middle East and North Africa.
The United States has said it is enlarging its assistance to Syria's fractured opposition. Also, according to Reuters, the White House will soon authorize greater covert assistance to the armed gangs.
Washington has already thrown its support behind Qatar, Saudi Arabia, and Turkey for arming the Syrian opposition.
Syria has been experiencing unrest since March 2011. The country says outlaws, saboteurs, and armed terrorists are the driving factor behind the unrest and deadly violence, while the opposition accuses the security forces of being behind the killings.
Western states have been calling for Assad to step down. However, Russia and China are strongly opposed to the Western drive to oust the Syrian president.
Damascus says that the chaos is being orchestrated from outside the country. There are reports that a very large number of the militants are foreign nationals.