Nikki Haley's comments in an interview airing Sunday came as part of an apparent shift in US policy towards Assad's government after the alleged chemical attack last week on the rebel-held town of Khan Sheikhun that killed 87 people, including many children.
Images of civilians suffering the apparent effects of a gas attack, including convulsions, vomiting and foaming at the mouth, provoked international outrage and prompted US President Donald Trump to order a strike on a Syrian airbase.
In the interview with CNN, Haley said peace in Syria was impossible with Assad in power.
"There's not any sort of option where a political solution is going to happen with Assad at the head of the regime," she told the "State of the Union" programme.
"If you look at his actions, if you look at the situation, it's going to be hard to see a government that's peaceful and stable with Assad."
"Regime change is something that we think is going to happen," she said, adding that Washington was also focused on fighting the Islamic State group in Syria and ending Iranian influence.
- Tillerson: IS fight top priority -
US Secretary of State Rex Tillerson insisted ahead of Moscow talks on Tuesday that defeating IS in Syria remained Washington's top priority.
"It's important that we keep our priorities straight. And we believe that the first priority is the defeat of ISIS," he told CBS television's "Face the Nation" being broadcast later Sunday.
Tillerson will also press Russia on its failure to prevent Syria using chemical weapons, he said in interviews aired Sunday.
"I don't draw conclusions of complicity at all, but clearly they've been incompetent and perhaps they've just simply been out-maneuvered by the Syrians," he told ABC's "This Week".
After years of calling for Assad's removal during former president Barack Obama's tenure, Washington appeared to be stepping back from seeking regime change in Syria in recent weeks.
Before the Khan Sheikhun attack, Tillerson said Assad's fate should be decided by the Syrian people, suggesting Washington would not oppose him standing for reelection.
But in the aftermath of the attack, Trump ordered the strike targeting the Shayrat air base in central Syria's Homs province with 59 Tomahawk missiles.
And his administration informed Congress that it could "take additional action, as necessary and appropriate, to further its important national interests".
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- Iran's Rouhani calls Assad -
Syria's government has denied any involvement in Tuesday's attack on Khan Sheikhun, suspected to be the second-deadliest chemical weapons attack since the country's war began in March 2011.
It killed at least 87 civilians, including 31 children, according to the Syrian Observatory for Human Rights, a Britain-based monitor.
Hundreds more suffered symptoms that the World Health Organization said were in some cases consistent with exposure to chemicals that include nerve gas.
The nature of the substance used has not been confirmed, and Syria has insisted it would not and has not used chemical weapons.
Assad's government signed the Chemical Weapons Convention and agreed to turn over its chemical armaments in 2013, after being accused of a sarin attack outside Damascus that killed hundreds of people.
But there have been repeated allegations of chemical weapons use by the government since then.
Syria's closest allies Russia and Iran have defended Damascus against the allegations of chemical weapons use, with Moscow saying a conventional strike hit a rebel depot containing "toxic substances".
Iran's President Hassan Rouhani called Assad to reaffirm his support for the Syrian leader in the wake of the US strike, Rouhani's office said on Sunday.
Rouhani said allegations that Assad's regime was behind a chemical weapons attack were "baseless" and suggested it was carried out by rebel groups to influence global public opinion.
Rouhani and Russian President Vladimir Putin also spoke by telephone about "the unacceptable nature of American aggression", a statement from Moscow said.
Both leaders also said they backed "an objective inquiry" into the Khan Sheikhun incident has also caused a diplomatic spat between Moscow and London.
British Foreign Secretary Boris Johnson has cancelled a trip to Russia over its support for Assad, prompting Moscow's foreign ministry to say London has "no real influence".
And on Sunday, British Defence Secretary Michael Fallon accused Russia of being responsible "by proxy" for deaths in the suspected chemical attack.
More than 320,000 people have been killed in Syria since the conflict began, and strikes have continued since the suspected chemical attack.
On Saturday, one woman was killed in a suspected Russian air strike on Khan Sheikhun, the Observatory said.
New strikes hit outside the town on Sunday, with no immediate reports of casualties, the monitor added.