"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 told a round-table of journalists, a day before John Kerry is 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 Assad's regime to help him defeat rebel forces. Its Lebanese proxy, Hezbollah, is also playing a bigger role in the conflict. "The Iranians are all in for Assad, and there is very little room for any kind of dialogue with them," Mrs Clinton said.
She spoke after Syria threatened to retaliate for an Israeli air strike, and its ally Iran warned ominously that the Jewish state 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. And Ali Abdul-Karim Ali, Assad's ambassador in Lebanon, said his government maintained "the option and the capacity to surprise in retaliation".
Mrs Clinton declined to talk specifically about Israel's strike, which US officials described as targeting trucks containing sophisticated Russian-made SA-17 anti-aircraft missiles. The trucks were next to a military research building, and the strike hit both the trucks and the facility, US officials said.
If the SA-17s were to have reached Hezbollah, they would have greatly inhibited the Israeli air force's ability to operate in Lebanon, where Israel has flown frequent sorties in recent years.
The attack has inflamed regional tensions already running high over Syria's 22-month-old civil war, and which has already led to deaths in neighbouring Turkey and Lebanon.