Air raid sirens sounded in Tel Aviv and Jerusalem early on Saturday, sending residents rushing into shelters as successive waves of Iranian missiles streaked across the skies.
A man and a woman were killed in Israel and dozens wounded by a missile that landed near their homes, Israel's ambulance service said.
Rescue teams were searching the rubble of apartment buildings that were destroyed in Rishon Lezion, a city outside of Tel Aviv.
Israel's Defence Minister Israel Katz said on Saturday the Iranian leadership had crossed a red line by firing at civilians and will "pay a heavy price for it".
In Iran, several explosions were heard in the capital Tehran.
The Fars news agency said two projectiles hit Tehran's Mehrabad airport, which hosts an air force base.
Iran's UN envoy Amir Saeid Iravani said 78 people, including senior military officials, have been killed in Israel's strikes on Iran and more than 320 wounded, most of them civilians.
Tehran launched waves of air strikes on Saturday after two salvos on Friday night, Fars reported. One of the waves targeted Tel Aviv, Israel's commercial hub, before dawn on Saturday, with explosions heard as far as Jerusalem, witnesses said.
Those were in response to Israel's attacks on Iran early on Friday against commanders, nuclear scientists, military targets and nuclear sites.
The US military helped shoot down Iranian missiles headed for Israel on Friday, two US officials said.
Israel's military said Iran fired fewer than 100 missiles on Friday and most were intercepted or fell short.
Several buildings in and around Tel Aviv were hit.
The Israeli strikes on Iran throughout the day and the Iranian retaliation raised fears of a broader regional conflagration, although Iran's allies Hamas in Gaza and Hezbollah in Lebanon have been decimated by Israel.
Iran's state news agency IRNA said Tehran launched hundreds of ballistic missiles at Israel after Israel blasted Iran's huge Natanz underground nuclear site and killed its top military commanders.
The above-ground pilot enrichment plant at Natanz had been destroyed, UN nuclear watchdog chief Rafael Grossi told the Security Council.
He said the UN was still gathering information about Israeli attacks on the Fordow fuel enrichment plant and a facility at Isfahan.
Iranian Supreme Leader Ayatollah Ali Khamenei accused Israel of starting a war, and a senior Iranian official said revenge would be painful.
Iran accused the US of being complicit in the attacks and said it shared full responsibility for the consequences.
Israel's UN envoy Danny Danon said intelligence had confirmed that within days Iran would have produced enough fissile material for multiple bombs. He called Israel's operation "an act of national preservation."
Iran has long insisted its nuclear program is for civilian purposes only.
The UN nuclear watchdog concluded this week that Iran was in violation of its obligations under the global non-proliferation treaty.
US President Donald Trump said it was not too late for Tehran to halt the Israeli bombing campaign by reaching a deal on its nuclear program.
Tehran had been in talks with the Trump administration on a deal to curb its nuclear program to replace one that Trump abandoned in 2018. Tehran rejected the last US offer.
Talks are due to resume in Oman on Sunday but Iran signalled it might not join.
with AP
