But Mattis also said the plan poses many unanswered questions, including whether it would be effective.
Speaking to reporters travelling with him to Copenhagen, Mattis said the borders of the proposed cease-fire areas are still being worked out, although the general locations are "well understood."
And he suggested that it's still not yet clear what impact the plan could have on the US-led fight against Islamic State militants.
"It's all in process right now," said Mattis, who was offering some of the first extensive public US comments on the agreement reached Friday by Russia, Turkey and Iran. "Who is going to be ensuring they're safe? Who is signing up for it? Who is specifically to be kept out of them? All these details are to be worked out and we're engaged."
The US is not part of the agreement, and the Syrian government and the opposition haven't signed on to the deal.
The plan, however, does not cover areas controlled by Islamic State group militants and US-backed Kurdish groups.
That leaves the US and its allies free to continue the campaign to retake IS-held territory. It doesn't, however, prevent frictions between Turkish troops and their Syrian allies from clashing or going after the US-backed Syrian Kurds.
"Will it affect the fight against ISIS? I think the international community is united in the sense of wanting to see ISIS put on its back foot."
Mattis was circumspect when asked if the plan had any hope of ending the brutal civil war that has killed some 400,000 people and displaced nearly half of the country's population since 2011.
"The devil is always in the details, right? So we have to look at the details, see if we can work them out, see if we think they're going to be effective," he said.
"All wars eventually come to an end. And we've been looking, for a long time, how to bring this one to an end."
The cease-fire is an effort to allow humanitarian aid to access hard-to-reach and besieged areas in Syria, were at least 4.5 million people in need reside.
The deal also calls for refugees to be allowed to return to the safe zones and services and infrastructure to be restored.
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