US President Donald Trump has warned the Syrian government and its Russian and Iranian allies against "recklessly" attacking rebel-held Idlib province.
In a tweet he warned of "a grave humanitarian mistake" in which hundreds of thousands of people could be killed.
President Bashar al-Assad of Syria must not recklessly attack Idlib Province. The Russians and Iranians would be making a grave humanitarian mistake to take part in this potential human tragedy. Hundreds of thousands of people could be killed. Don’t let that happen!— Donald J. Trump (@realDonaldTrump) September 3, 2018
Syrian government forces are said to be preparing a huge offensive on the last major rebel stronghold in the country.
The UN said such a campaign could have disastrous consequences for thousands of civilians.
The US State Department also warned that Washington would respond to any chemical attacks by the Syrian government or its allies.
"All eyes on the actions of Assad, Russia, and Iran in Idlib. #NoChemicalWeapons," US ambassador to the UN Nikki Haley tweeted.
With rebels defeated in most of Syria, the offensive in the northern province could prove to be the last major battle of the Syrian civil war.
According to a UN estimate, there are about 10,000 al-Nusra and al-Qaeda jihadist fighters still holding out in Idlib.
Sources quoted by Reuters news agency said that President Bashar al-Assad was preparing a phased offensive.
Russian Foreign Minister Sergei Lavrov said "terrorists" must be wiped out in Idlib, accusing them of using civilians as human shields.
Both he and his Syrian counterpart, Walid Muallem, have accused rebels of preparing to stage a chemical attack in Idlib in order to blame pro-government forces and draw new US military retaliation.
Kremlin spokesman Dmitry Peskov said that recent naval drills off Syria were justified, and that the "hotbed of terrorists" in Idlib must be tackled.
However, UN envoy to Syria Staffan de Mistura has warned of a "perfect storm" if the government goes ahead with its threatened offensive.
He called for humanitarian corridors to be set up to allow civilians to be evacuated temporarily.
The jihadists must be defeated, Mr de Mistura said, but not at the expense of thousands of civilian lives.
"There is a perfect storm based on warnings, counter-warnings which is gathering around and due to the dilemma, which is a true dilemma on how to defeat terrorists in Idlib and at the same time avoid affecting a huge number of civilians," he said.
"So, while we are aware that efforts and discussions are taking place to avoid the worst-case scenario, one cannot ignore that miscalculations may indeed occur leading to unforeseen escalation and we are all very much concerned."
The UN is desperate to avoid the deaths of civilians seen recently in other parts of Syria such as Aleppo, Raqqa or the Eastern Ghouta, and its diplomats are appealing for all sides to show restraint.
Mr de Mistura offered to go to Idlib personally to set up a humanitarian corridor which, he acknowledged, would mean evacuating people into government-controlled territory.
How costly for human life has the civil war been?
After more than seven years of fighting, more than 400,000 people are dead or missing, and more than half the population have been driven out of their homes.
Idlib has been a haven for rebels and their families evacuated out of areas won back by the government, but there is no obvious place for them to move to within Syria if they abandon the province now.
Any offensive on Idlib could raise tensions with Turkey, which maintains observation posts around rebel territory as part of a "de-escalation deal" with Russia and Iran.
Iran is to host a summit later this week at which the leaders of Iran, Russia and Turkey will discuss Idlib, Fars news agency reported.