Speaking to journalists on Friday, the Pentagon chief said he did not know how it would start but an escalation between the two rivals is likely because of Iran’s links with Hezbollah, who are operating in the area.
He said: "I can see how it might start, but I am not sure when or where.
“Conflict between the two countries in Syria is very likely… because Iran continues to do its proxy work there through Hezbollah."
Israeli Defense Minister Avigdor Lieberman met with Mr Mattis after the hearing.
Mr Liberman also met with US National Security Adviser John Bolton, who he called a "loyal friend to the state of Israel”.
Tensions between Israel and Iran have escalated since airstrikes against Iranian bases in Syria on April 9 and April 17.
Syrian state-TV blamed the strikes on Israeli forces, but Israel has neither confirmed nor denied the attacks.
Avigdor Lieberman has vowed to protect his country against "Iran’s aggression" and refused to rule out breaching Syrian airspace to launch future attacks.
Mr Lieberman claimed Israel has “total freedom of action” in Syrian airspace if necessary.
He told Walla News: “We will maintain total freedom of action.
"We will not accept any limitation when it comes to the defence of our security interests.
“All options are on the table."
Tensions were escalated further after the US, France and UK carried out missile strikes against Iranian ally Syria on April 13.
Mike Pompeo also said it was “unlikely” Trump would keep the US in the Iran deal during the news conference at Nato headquarters.
This seemed to support Macron's claims that Trump is considering pulling out of the deal.
Mr Macron said: "My view — I don't know what your president will decide — is that he will get rid of this deal on his own, for domestic reasons.
"If you heard him in the Oval Office, you will have come to the same conclusions," he said before pointing out that ripping up the Iran deal was one of Trump's campaign promises.”
