In an interview, 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.