In an interview on Tuesday, Mr Trump said defeating Isis is more important for him than persuading Syrian President Bashar al-Assad to resign.
"What we should do is focus on Isis. We should not be focusing on Syria," Mr Trump said. "You're going to end up in World War Three over Syria if we listen to Hillary Clinton."
"Assad is secondary, to me, to Isis," he said, adding that the Syrian President was far stronger than he had been three years ago.
"You're not fighting Syria any more, you're fighting Syria, Russia and Iran, all right? Russia is a nuclear country, but a country where the nukes work as opposed to other countries that talk."
Mr Trump also slammed Ms Clinton's handling of US-Russian relations, questioning her ability to negotiate with Russian President Vladimir Putin after heavily criticising him.
"How she is going to go back and negotiate with this man who she has made to be so evil?" he said.
Ms Clinton has supported the creation of a no fly zone and “safe zones” on the ground in Syria, which in the third presidential debate she said would "save lives and hasten the end of the conflict".
Responding to Mr Trump's comments, a spokesman for Ms Clinton said both Republican and Democratic national security experts have criticised Mr Trump as unfit to be commander-in-chief.
"Once again, he is parroting Putin's talking points and playing to Americans' fears, all while refusing to lay out any plans of his own for defeating Isis or alleviating humanitarian suffering in Syria," Clinton spokesman Jesse Lehrich said in a statement.
Ms Clinton's no fly-zone policy would significantly increase US involvement in the Syrian conflict and has been rejected by US President Barack Obama.
Chris Wallace, moderator of the third presidential debate, raised warnings about the no-fly zone from critics, including the Chairman of the Joint Chiefs Marine Gen Joseph Dunford, that it could bring about a military conflict with Russia.
“If you impose a no-fly zone, how do you respond to their concerns?” Mr Wallace asked. “Secondly, if you impose a no-fly zone and a Russian plane violates that, does President Clinton shoot that plane down?”
Ms Clinton argued that protecting civilians in areas of Syria under air strikes from Syrian and Russian forces would “help us in our fight against Isis,” but did not directly say what her actions would be if a Russian aircraft breached the zone’s parameters.
Mr Trump's remarks come just two weeks before the 2016 presidential election as he trails in the national polls against Ms Clinton, following widespread allegations of his involvement in sexual assault.
In recent weeks, Mr Trump has claimed there was widespread voter fraud and the election was “rigged” against him, suggestions Mr Obama has called “dangerous” and damaging to democracy.
Additional reporting by Reuters
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