Mattis spoke in a press gaggle en route to Rome, where he will join about a dozen members of the US-led coalition fighting Islamic State will meet at a conference to discuss the fight against the group.
"Israel has an absolute right to defend itself, and I think that's what happened yesterday," he said in response to a question about Saturday's military crisis, warning also about a growing Iranian influence in the region.
"So when Syria, which has made no... excuse for what they're doing alongside Iran, when they are providing throughout for Iran to give weapons, including more sophisticated weapons, to the Lebanese Hezbollah, Israel has an absolute right to defend themselves," he stated.
"If you live in the region, there's no doubt what Iran is doing."
On Saturday morning, an Iranian drone took off from the Tiyas Military Air Base, aka the T4 Air Base, deep in the Syrian province of Homs. The drone was spotted by Israel, and residents across the Golan Heights and the Jordan Valley were woken by air raid sirens that sounded when an Israel Air Force Apache attack helicopter intercepted the unmanned aerial vehicle near Beit She’an.
In response, Israeli jets took off to strike the drone’s launch site, and were met by massive Syrian anti-aircraft fire. The two crew members of one of the Israeli F-16s saw that one missile had locked onto their aircraft, and they ejected from the jet, which crashed near Kibbutz Harduf in the Lower Galilee.
The incident was viewed as a significant event by the IDF, which warned that the Iranians and Syrians were “playing with fire.”
Mattis, who previously served as served as the commander of the United States Central Command, said he saw the Israeli response as a proactive one.
"They don't have to wait until their citizens are dying under attack before they actually address that issue," he said.
US Secretary of State Rex Tillerson, who is currently visiting the Middle East, may still yet visit Israel due to the security situation.
Anna Ahronheim and Reuters contributed to this report.