President Obama has said the coming weeks will be "critical" for Syria's future, ahead of a two-week truce due to start on Friday.
He warned Russia that all parties to the cessation of hostilities needed to stop attacks, including air strikes.
If successful, he said, the truce could be a first step towards ending the chaos and violence in Syria.
And he vowed to defeat the so-called Islamic State (IS), which he said was "not a caliphate but a crime ring".
Mr Obama said the success of the cessation of hostilities would depend on whether parties including the Syrian government, Russia and their allies lived up to their commitments.
Attacks needed to end and humanitarian aid had to be allowed through to desperate civilians, he said.
"The coming days will be critical and the world will be watching," he said.
Earlier, Russian Foreign Minister Sergey Lavrov said he hoped the US would respect the truce.
Mr Obama said that factional rivalry among the rebels, as well as the campaign against IS, meant there would be no immediate end to violence.
He also insisted that Syrian President Bashar al-Assad had to step down from power as part of any solution to Syria's civil war, but acknowledged there was "significant dispute" with Russia and its allies over this point.
"It is clear that after years of barbarity against his people, many will not stop fighting until Assad is out of power," he said.
Mr Obama also said progress was being made in the fight against IS, but added that the only way to inflict a lasting defeat on the group was to bring an end to the Syrian conflict.
IS had not had a single successful offensive operation in Syria or Iraq since last summer
The group has lost 40% of its territory
The flow of foreign fighters to IS in Syria was slowing
"More people are realising that IS is not a caliphate, it's a crime ring. They are not winning over hearts and minds, they are under pressure," he said.
"In the end the brutality of IS is no match for the yearning of millions who want to live in safety and dignity."
Syria's main opposition umbrella group said that it was ready for a two-week truce to test the government's commitment to the plan.
But the High Negotiations Committee expressed concern that Moscow and Damascus would continue targeting rebels allied to the al-Nusra Front, a jihadist group that, along with IS, will be excluded from the cessation of hostilities.
The Kurdish Popular Protection Units (YPG), a militia that controls territory in northern Syria near the Turkish border, said on Thursday that it would respect the truce, but reserve the right to retaliate if attacked.
The UN special envoy to Syria, Staffan de Mistura, meanwhile said he would be announcing the date for the next round of peace talks in Geneva on Friday.
Syria conflict: Obama says next few weeks 'critical'
Reviewed by James chibueze