He also said the US should focus on defeating so-called Islamic State (IS) rather than removing Syria's president.
Mrs Clinton has proposed a no-fly zone over Syria. The top US military chief has said that could spell conflict with Russian jets in the region.
The Clinton campaign accused Mr Trump of "playing to Americans' fears".
Mr Trump also attacked Republicans for not uniting behind his candidacy.
"If we had party unity, we couldn't lose this election to Hillary Clinton," he told Reuters news agency at Trump National Doral golf resort in Miami, Florida.
The Republican standard-bearer struck an apocalyptic tone when criticising his Democratic rival's plan to control Syrian air space.
"You're going to end up in World War Three over Syria if we listen to Hillary Clinton," Mr Trump said.
"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 suggested there should be a refocus away from the long-held US position of trying to remove Syrian President Bashar al-Assad, saying: "What we should do is focus on IS. We should not be focusing on Syria."
He also suggested Mrs Clinton would be unable to talk with Russian President Vladimir Putin after her sharp criticism of him.
Mr Trump questioned "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.
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