The US fired approximately a dozen interceptors at the Iranian missiles fired towards Israel, the Pentagon has said.
US National Security Adviser Jake Sullivan called it a “significant escalation by Iran”.
The Israeli military said about 180 missiles were fired at Israel on Wednesday, most of which were intercepted.
Iranian President Massoud Pezeshkian has defended the attack, calling it a “decisive” response “in defence of Iranian interests and citizens”.
In a Pentagon press briefing on Tuesday, Maj Gen Patrick Ryder said two US Navy destroyers were used to fire the interceptors at the missiles, which the US believed were all launched from Iran.
He did not confirm whether they hit any of the Iranian missiles used in the attack – adding that information was yet to be established.
He said Tuesday’s attack was about “twice the scope” of Iran’s April attack in terms of the ballistic missiles used.
Maj Gen Ryder added that the Pentagon was not aware of any warning for the attack.
Speaking at a separate White House briefing, Mr Sullivan described the attack as a “significant escalation by Iran”, adding that it was “equally significant that we were able to step up with Israel and create a situation in which no-one was killed in this attack in Israel”.
He added that the US would now consider “the appropriate next steps” to secure American interests and “to promote stability to the maximum extent possible”.
Iran’s Islamic Revolutionary Guard Corps (IRGC) said in a statement that the attacks were in response to Israel’s killing of a top IRGC commander and leaders of Iran-backed militias in the region.
It mentioned the killings of Hezbollah chief Hassan Nasrallah and IRGC commander Abbas Nilforoshan in Lebanon last weekend.
It also referenced the killing of Hamas political leader Ismail Haniyeh in Tehran in July. While Israel has not admitted to being behind Haniyeh’s death, it is widely believed to be responsible.