This comes at a time when Israel has been warning of the increased Iranian involvement along its border in Syria and Lebanon.
The two pilots parachuted to safety before the crash in northern Israel.
Red alert sirens could be heard in areas of northern Israel and the Israeli-occupied Golan Heights due to Syrian anti-aircraft fire.
Israel’s chief military spokesman, Brigadier General Ronen Manelis, said: “This is a serious Iranian attack on Israeli territory. Iran is dragging the region into an adventure in which it doesn’t know how it will end.
“Whoever is responsible for this incident is the one who will pay the price.”
Citizens reported hearing a number of explosions and heavy aerial activity in the area near Israel’s borders with Jordan and Syria.
This has been the most serious incident between Israel and Iran since the start of the civil war in Syria in 2011.
It is the first time Israel has acknowledged attacking Iranian targets in Syria since the war began.
Israel has repeatedly warned in recent weeks against the presence of Iranian forces in neighbouring Syria.
The Israeli military “targeted the Iranian control systems in Syria that sent the UAV (unmanned aerial vehicle) into Israeli airspace. Massive Syrian anti-air fire, one F16 crashed in Israel, pilots safe,” spokesman Lieutenant Colonel Jonathan Conricus tweeted.
Israel has long complained about the involvement of archenemy Iran, and Iranian proxy Hezbollah, in the Syria war.