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."
Washington backed Israel and blamed Iran for the escalation.
United Nations Secretary-General Antonio Guterres called for "an immediate and unconditional de-escalation of violence" in Syria, UN spokesperson Stephane Dujarric said in a statement.
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-defense in response to the strikes.
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 recent years, Conricus told journalists.
Israel said its reprisals were "large-scale" raids on Syrian air defense 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.