US Senate majority leader Chuck Schumer has called for new elections in Israel, accusing Prime Minister Benjamin Netanyahu of prioritising his "political survival" above the country.
Mr Schumer, a Democrat and the highest-ranking Jewish official in the US, said Mr Netanyahu had "lost his way".
He warned that huge civilian casualties in Gaza risked alienating allies and turning Israel into a global "pariah".
It is a sharp escalation in US criticism of Mr Netanyahu's government.
Officials in Washington, including President Joe Biden, have broadly avoided directly criticising Mr Netanyahu's approach to the conflict, which began when Hamas gunmen stormed into southern Israel on 7 October, killing about 1,200 people and taking 253 others hostage.
However, cracks have begun to emerge in the coalition in recent weeks, with the president warning Israel against expanding its invasion into the city of Rafah, which he called a "red line".
Nonetheless, the White House was quick to distance itself from Mr Schumer's comments. Spokesperson John Kirby said that while the Senate leader had a right to his opinion, administration officials were focused on working with Israel on its defence.
Speaking in the Senate on Wednesday, Mr Schumer, a long-time supporter of Israel, harshly criticised the Israeli leader, who he said had come to allow "his political survival to take precedence over the best interests of Israel".
Israel, Mr Schumer said, must make "course corrections" and take steps to better protect civilians in Gaza.
More than 30,000 Palestinians - the majority of them children and women - have now been killed in Gaza since 7 October, the Hamas-run health ministry said last month.
The actual number of dead is likely to be far higher as the count does not include those who have not reached hospitals, among them thousands of people still lost under the rubble of buildings hit by Israeli air strikes.
Mr Netanyahu said on Sunday that he could not accept the figure of 30,000. He said Israel's military had killed 13,000 Hamas fighters in Gaza and that it estimated the ratio of civilian deaths to combatant deaths was 1 to 1.5.
"As a democracy, Israel has the right to choose its own leaders, and we should let the chips fall where they may," Mr Schumer said. "But the important thing is that Israelis are given a choice. There needs to be a fresh debate about the future of Israel."
"In my opinion, that is best accomplished by holding an election," he added. Israel is next due to hold a general election by October 2026.
For peace talks to advance, Mr Schumer said Palestinian Authority President Mahmoud Abbas, who is based in the occupied West Bank, must also step down. The Palestinian leader, who is 88, has been little seen throughout the conflict and his government has not held elections since 2006.
On Wednesday, Mr Abbas, who has been under pressure from the US to reform the Palestinian Authority, appointed his former adviser as prime minister.
Mr Schumer's comments prompted a rebuke from outgoing Republican Senate Leader Mitch McConnell, who called the 40-minute speech "grotesque" and "unprecedented".
He said it was "hypocritical for Americans who hyperventilate about foreign interference in our own democracy to call for the removal of a democratically elected leader of Israel".
Israel's ambassador in Washington, Michael Herzog, also attacked the remarks, writing on X that it was "unhelpful" and "counterproductive" to comment on "the domestic political scene of a democratic ally".
While the US remains Israel's closest ally and biggest provider of military aid, concerns have been mounting within the Biden administration at its prosecution of the war in Gaza. In his State of the Union address, Mr Biden called Israel's response in the territory "over the top".
The president has also become more and more vocal in calling for Israel to let much more humanitarian aid into the territory, with "no excuses".
But, in a sign of the deepening rift between the two men, Mr Netanyahu hit back at Mr Biden, maintaining that his government and policies had the support of the Israeli people.
Mr Biden recently accused Mr Netanyahu of "hurting Israel more than helping Israel", which led Mr Netanyahu to describe that assertion as "wrong".
Opinion polls show most Israelis support the war, but one survey released in January suggested just 15% of voters wanted Mr Netanyahu to remain in office once the conflict ends.
In a statement issued following Mr Schumer's remarks, Mr Netanyahu's Likud party insisted that the prime minister was "supported by a huge majority of the people".
"It is expected of Senator Schumer to respect Israel's elected government and not undermine it. This is always true, but even more so during wartime," it added.
Meanwhile, the US revealed sanctions against three more settlers and for the first time against two Israeli settlement outposts it accused of undermining stability in the occupied West Bank.
There were nearly 500 Israeli settler attacks against Palestinians between 7 October and 31 January, according to UN figures.
The vast majority of the international community considers the settlements and outposts illegal under international law, though Israel and the US dispute this interpretation.
