Prime Minister Riad Hijab reportedly defected to Jordan with three other ministers, as well as his family.
Hijab is the highest-level government official to defect since the uprising against Assad's authoritarian rule began 17 months ago. The other ministers' identities were not immediately known.
"The prime minister defected from the regime of killing, maiming and terrorism. He considers himself a soldier in the revolution," Mohammad Otari, Hijab's spokesman, told The Associated Press in Amman, Jordan.
Hijab's defection comes less than two months after he was appointed to the post, which is largely symbolic in Syria where the president and a tight coterie of advisers hold the real power.
He said the prime minister approached rebels from the Free Syrian Army at least two months ago to help him escape, which they did.
Earlier Monday, Syrian state-run TV reported Hijab was fired from his post. A former agriculture minister, Hijab took office less than two months ago and was considered a loyalist in Assad's ruling Baath party.
With Syrian diplomacy all but dead, the Obama administration is shifting its focus on the civil war away from political transition and toward helping the rebels defeat the Syrian regime on the battlefield.
The U.S. still wants to avoid any military involvement, banking on a complicated policy of indirect assistance to the rebels and hope that the ragtag alliance of militias can demoralize President Bashar Assad's better-armed forces and end the war without far greater casualties.
The defections are "the latest indication that Assad has lost control of Syria and that the momentum is with the opposition forces and the Syrian people," White House spokesman Tommy Vietor said.
"The regime is crumbling," State Department spokesman Patrick Ventrell said.
The Associated Press contributed to this report.