President Joe Biden has promised Israel "ironclad" US support amid fears that Tehran could launch reprisals for an attack that killed senior Iranians.
Mr Biden warned that Iran is threatening to launch a "significant attack" after Israel struck the Iranian consulate in Syria 10 days ago.
"We're going to do all we can to protect Israel's security," he added.
Earlier on Wednesday, Iran's leader said the Israeli attack in Damascus was equivalent to an attack on Iran itself.
"When they attacked our consulate area, it was like they attacked our territory," Ayatollah Ali Khamenei said in a televised speech."The evil regime must be punished, and it will be punished."
It is unclear what form any reprisal attack would take.
For Iran to strike Israel directly would risk an even greater escalation in the conflict, and analysts have said Iran does not have the military capability for a significant confrontation.
A possible alternative is an attack via an Iranian proxy like Hezbollah, which has traded fire with Israel across the border from Lebanon almost daily since 8 October. Those exchanges have intensified in recent weeks.
"Hezbollah is very capable, hundreds of thousands of rockets and missiles there, on the border that can reach all the way into southern Israel," Joe Buccino, former Communications Director at the US military's Central Command, told the BBC."Hezbollah is much more capable than Hamas. So they'd have the capability to do significant damage into Israel."
On Sunday an Iranian official warned Israel's embassies were "no longer safe", suggesting a consulate building could be a possible target.
Experts have also suggested Iran could target Israel with a cyber-attack.
Thirteen people were killed in the 1 April attack on the Iranian consulate building, including senior Iranian military leaders. Among them was Brig-Gen Mohammad Reza Zahedi, a senior commander of Iran's elite Quds Force in Syria and Lebanon.Israel has not claimed responsibility for the attack, but is widely considered to have been behind it.
US and Israeli forces in the region have been put on high alert in the days since. Last week the Israel Defense Forces (IDF) cancelled leave for soldiers serving with combat units and called up reservists to bolster air defence units.
Israeli Minister of Foreign Affairs Israel Katz responded on social media to Ayatollah Khamenei's comments by saying if Tehran attacked from its territory, Israel would react and "attack in Iran".
Meanwhile the head of US forces in the region, Gen Michael Kurilla, is to discuss the threat of a possible Iranian attack in talks with Israeli Defence Minister Yoav Gallant and army Chief of Staff Lt Gen Herzi Halevi in Israel on Thursday, according to Israeli media reports.
Mr Biden's remarks came as he was speaking to journalists at the White House on Wednesday alongside Japanese Prime Minister Fumio Kishida.
"As I told Prime Minister [Benjamin] Netanyahu, our commitment to Israel's security against these threats from Iran and its proxies is ironclad - let me say it again, ironclad," Mr Biden said.
His comments come one day after an interview, recorded a week ago, was aired in which Mr Biden urged Mr Netanyahu to "just call for a ceasefire" in Gaza and in which he said he disagreed with the prime minister's war strategy.
"I think what he's doing is a mistake. I don't agree with his approach," he said in the interview with US network Univision.
It also comes days after a tense phone call between Mr Biden and Mr Netanyahu in the wake of the Israeli killing of seven humanitarian aid workers in Gaza.
Mr Biden has sharpened his rhetoric over Israel's conduct in the nearly six-month-old war sparked by Hamas's 7 October attack, and voiced his growing frustration with Mr Netanyahu. Iran backs Hamas and Iranian officials have praised the attack in which about 1,200 people were killed and 253 taken to Gaza as hostages.
US officials have been attempting to send a message to the Iranians that, despite differences of opinion between Mr Biden and Mr Netanyahu, any attack on Israel will be met with an aggressive US response.
In an effort to ease tensions, the foreign ministers of Saudi Arabia, the UAE, Qatar and Iraq spoke to their Iranian counterpart this week, according to Axios.
The ministers were asked to convey a message from Mr Biden's senior Middle East advisor, Brett McGurk, about the need to de-escalate.
Additional reporting by Raffi Berg
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