Trump has warned that an attack "would be a reckless escalation of an already tragic conflict", the White House said, risking the lives of hundreds of thousands of people.
"Let us be clear, it remains our firm stance that if President Bashar al-Assad chooses to again use chemical weapons, the United States and its Allies will respond swiftly and appropriately", said White House Press Secretary Sarah Sanders.
On Tuesday the United Nations special envoy for Syria, Staffan de Mistura, said panic was spreading among the 3 million citizens of Idlib province as he suggested the Assad government and its allies had set 10 September as the date for a full-scale bombardment of the last large rebel enclave.
"If they want to continue to go the route of taking over Syria, they can do that, but they cannot do it with chemical weapons", she said.
Located near the Turkish border, Idlib is home to more than 3 million Syrians, many of whom fled from other cities following attacks by regime forces.
"Let's try to avoid that the last probably major battle of the Syrian territorial conflict...ends in a bloodbath", he told reporters in Geneva, insisting Russian Federation and Turkey held "the key for the soft solution to the Idlib issue". "The Russians and Iranians would be making a grave humanitarian mistake to take part in this potential human tragedy".More news: EPL: Hazard predicts team that will win title
The verbal clash came as towns and villages in the northern Idlib province, where Syria's rebels are holed up, came under intense airstrikes, killing at least eight people, according to a search and rescue group and a conflict monitoring group.
De Mistura said there were an estimated 10,000 fighters with UN-designated terror groups now in Idlib.
The Syrian military has been deploying reinforcements to the zone for more than a month, and Russian Federation has stepped up its rhetoric.
But he stressed that there are some 2.9 million civilians in the province - including about a million children who "are not terrorists".
The Trump administration said Tuesday that any reckless action taken by the President Bashar al-Assad and his regime's allies would incur the United States' ire.
Mattis reportedly told Trump he would get "right on it" in an apparent attempt to pacify the president, but hung up the phone and instead told a senior aide, "We're not going to do any of that".