After a crowd attacked the US embassy in Damascus on Monday, Mrs Clinton said Mr Assad was "not indispensable".
France also blamed the regime after its embassy was similarly targeted.
The attacks have since been condemned by the UN Security Council, which called on Damascus to protect diplomatic property and personnel.
Syria's state news agency Sana said Mrs Clinton's remarks "amount to further proof of the flagrant interference of the US in the internal affairs of Syria".
President Barack Obama echoed Mrs Clinton's comments late on Tuesday, telling CBS that "increasingly you're seeing President Assad lose legitimacy in the eyes of his people".
The embassy attacks came after the US and French envoys visited the northern city of Hama - a focus of anti-government unrest - last week, to show solidarity with residents facing a security crackdown. Syria said they had sought to incite the protests.
Human rights groups say at least 1,400 civilians and 350 security force personnel have been killed since anti-government demonstrations across Syria began in mid-March.
The Syrian government denies targeting civilians, saying it is tackling armed groups.
Embassy attacksPro-government demonstrators have held protests outside the US and French embassies in the Syrian capital for the past two days.
Hillary Clinton: "We have absolutely nothing invested in President Assad remaining in power"On Monday, three staff members at the French embassy were injured after protesters used a battering ram to try to enter the building. The protesters broke windows and replaced the French tricolore with the Syrian national flag.
The residence of the US ambassador, Robert Ford, was also briefly attacked.
President Obama said Washington had "sent a clear message that nobody can be messing with our embassy and that we will take whatever actions necessary in order to protect our embassy".
In the strongest criticism from Washington to date, Mrs Clinton said: "President Assad is not indispensable and we have absolutely nothing invested in him remaining in power... Our goal is to see that the will of the Syrian people for a democratic transformation occurs."
Syrian officials denounced the remarks in a statement on Tuesday.
"The political leadership [of Syria] does not draw its legitimacy from the United States, but solely from the will of the Syrian people," it said.
Syria expects the US and its envoys "to refrain from any actions that are liable to provoke the sentiments of Syrians and their attachment to their national independence".
In a statement also issued on Tuesday, the UN Security Council said it condemned the attacks "in the strongest terms".
"Members of the security council recall the fundamental principle of the inviolability of diplomatic missions and the obligations on host governments, including under the 1961 Vienna Convention on Diplomatic Relations, to take all appropriate steps to protect embassy premises," the statement said.
"In this context, the members of the Security Council call on the Syrian authorities to protect diplomatic property and personnel."
Dialogue endsThe diplomatic spat coincided with the close of a government-organised dialogue conference in Damascus that many opposition leaders have boycotted.
In the final statement from the two-day meeting, participants said that dialogue was the only way out of the current crisis.
It called for the immediate release of political prisoners and all those arrested during the past five months of unrest, and for a democratic and pluralistic Syria.
However, the statement rejected all kinds of foreign interference.
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