Following the most serious confrontation between arch foes Israel and Iran since Syria's civil war began in 2011, Prime Minister Benjamin Netanyahu vowed to prevent Tehran from establishing a threatening military presence in the Arab state.
Israel's raids came after it intercepted what it said was an Iranian drone entering its airspace from Syria, calling it an "attack".
It was the first time Israel has publicly acknowledged targeting what it identified as Iranian positions in Syria since the conflict started.
Iran denounced Israeli "lies" and said Syria had the right to self-defence in response to the strikes.
Israeli soldiers inspect the remains of an F-16 that crashed in northern Israel. Source: EPA
Separately, Iran issued a statement with Syria's other main allies - Russia and Lebanese militant group Hezbollah - denying Israel's drone allegations.
Russia's foreign ministry urged "restraint" by all parties, adding it was "unacceptable to create threats to the lives and security of Russian soldiers" in Syria.
Israeli military spokesman Jonathan Conricus warned that Syria and Iran were "playing with fire", but stressed that his country was not seeking an escalation.
"This is the most blatant and severe Iranian violation of Israeli sovereignty in the last years," Conricus told journalists.
'12 targets attacked'
Israel said its reprisals after the exchange were "large-scale" raids that attacked Syrian air defence systems and Iranian targets.
"Twelve targets, including three aerial defence batteries and four Iranian targets that are part of Iran's military establishment in Syria were attacked," a military statement said.
Israel has repeatedly warned against the presence of Iranian forces in Syria.
The two crew from Israel's crashed F16 were alive after ejecting, although one was severely wounded, the military said.
They landed inside Israel and were taken to hospital.
Israel's military said the confrontation began with the drone entering its airspace before being intercepted by a combat helicopter.
Conricus said it was intercepted well inside Israel north of the city of Beit Shean, near the Jordan border.
He did not say whether the drone was armed, but alleged it "was on a military mission sent by Iranian military forces" from an "Iranian base" in the Palmyra area.
Eight Israeli aircraft then "targeted the Iranian control systems in Syria that sent the UAV" and confirmed hits, Conricus said.
He said the aircraft met "massive Syrian anti-air fire", and the F16 later came down in northern Israel's Jezreel valley, probably as a result of the anti-aircraft fire.
Damascus said its air defences repelled two Israeli raids on its military bases in central Syria, hitting more than one warplane during the first.
'Israel wants peace'
The Syrian Observatory for Human Rights, a Britain-based monitor, said Israel had targeted several bases in the east of the central province of Homs.
It said the bases are used by both Iranians and Russians deployed in support of the regime.
Syrian state media said the later raids targeted positions in the south.
Iranian foreign ministry spokesman Bahram Ghasemi said that "to cover their crimes in the region, Israeli officials are resorting to lies against other countries".
"Iran does not have a military presence in Syria, and has only sent military advisers at the request of the Syrian government," he said.
The statement from Iran, Russia and Hezbollah dismissed Israel's drone allegations as "lies".
It said Israel had targeted drones used against "terrorist organisations", mainly the Islamic State group.
Hezbollah in a separate statement said the F16's downing marked the start of a "new strategic era".
Danny Danon, Israel's ambassador to the UN, called on the Security Council "to condemn this dangerous act and to put an immediate end to Iranian provocations".
Speaking after meeting defence officials, Netanyahu reiterated that Israel would not allow Iran to establish itself militarily in Syria.
"Israel wants peace but we will continue to defend ourselves with determination against any attack on us and against any attempt by Iran to entrench itself militarily in Syria or anywhere else," he said late Saturday.
Netanyahu also said he had spoken with Russian President Vladimir Putin.
"I reiterated our right and duty to defend ourselves against attacks from Syrian territory," Netanyahu said, adding that they agreed to continue their coordination on Syria.
The Kremlin said Putin had stressed to Netanyahu the necessity to "avoid any measure that could lead to a dangerous escalation".
Still at war
Netanyahu said he also spoke to US Secretary of State Rex Tillerson, who is about to embark on a visit to the region.
The premier has held a series of talks in recent months with Putin in a bid to persuade Russia to limit Iran's presence near Israel.
Israel is technically at war with Syria and occupies a swathe of the strategic Golan Heights that it seized in the Six-Day War of 1967 and later annexed in a move never recognised by the international community.
Israel has sought to avoid direct involvement in the Syria conflict, but acknowledges carrying out dozens of air strikes there to stop what it calls deliveries of advanced weaponry to Hezbollah.
Analysts said they did not expect a further escalation for now, but suggested the heavy anti-aircraft fire showed Syria was more emboldened to counter Israel's strikes.
Ofer Zalzberg of the International Crisis Group said Russia should mediate since "it is the only stakeholder which has strong relations with all sides today".
But he said "this incident signals a new phase in a way of the war in Syria".
