Mrs Clinton said Iran's involvement heightened the danger of a larger regional conflict drawing in Israel or other neighbours.
"I've done what was possible to do," she told reporters on the eve of her last day in office. But she painted a harrowing picture of a war that could still get worse.
"The worst kind of predictions about what could happen internally and spilling over the borders of Syria are certainly within the realm of the possible now," she said.
The conflict "is distressing on all fronts", Mrs Clinton said, a day before John Kerry was sworn in as her successor.
She pointed the finger primarily at Iran, accusing it of dispatching more personnel and better military material to President Bashar al Assad's regime to help him defeat rebel forces.
Mrs Clinton spoke after Syria threatened to retaliate for a suspected Israeli airstrike, and its ally Iran warned Israel would regret the attack.
In a letter to the United Nations secretary general, Assad's regime stressed its "right to defend itself, its territory and sovereignty" and holding Israel and its supporters accountable.
l The UN refugee agency said yesterday it had reached the opposition-held Azaz area of northern Syria, where it found an estimated 45,000 displaced people living in camps.