The Republican Presidential candidate said Hillary Clinton’s call for no-fly zone in Syria would lead to conflict with Russia.
Mrs Clinton has called for no-fly zones and safe zones in a bid to bring the five year conflict to an end, a proposal which has also been championed by leading Republicans in Congress.
The controversial plans which President Barack Obama and others have opposed could directly lead the US into conflict with Russia.
Mrs Clinton outlined her support for the no-fly zone proposal during the final presidential debate in Nevada on 20 October.
A US enforced no-fly zone would raise the prospect the US could shoot down a Russian jet entering Syrian airspace.
Mr Trump said: “What we should do is focus on Isis. We should not be focusing on Syria.
“You’re going to end up in World War Three over Syria if we listen to Hillary Clinton.
“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 added that getting President Assad to leave power was not as important as tackling Isis.
“Assad is secondary, to me, to Isis,” he told Reuters news agency at Trump National Doral golf resort in Miami, Florida.
He was particularly critical of Clinton’s handling of relations with Russian President Vladimir Putin.He claimed that her tough stance and harsh criticism while Secretary of State meant it would be tough for her to deal with Putin.
Mr Trump said “how she is going to go back and negotiate with this man who she has made to be so evil” if she is elected president on 8 November.
Mr Trump also attacked Republican Party in-fighting which he claimed damaging his campaign.
“If we had party unity, we couldn’t lose this election to Hillary Clinton.
“The people are very angry with the leadership of this party, because this is an election that we will win 100% if we had support from the top. I think we’re going to win it anyway,” he added.
The interview comes two weeks before the November 8 election with Mr Trump trailing badly in the polls.
He again repeated claims of election rigging and media bias against his campaign, while praising the turn out of Trump supporters.