Scores of delegates trooped out of the hall in protest.
Netanyahu addressed the plenum after days of speeches by world leaders condemning Israel's war in Gaza and accusing him of orchestrating a genocide against the Palestinian people.
At times, the Israeli leader, facing a tough race for re-election in October, became emotional and indignant as he lectured his critics, among them New York's mayor.
Netanyahu said attacking Iran "was one of the easiest decisions I've ever had to make" and denounced as "moral cowards" a mass of delegates who walked out of the hall when he took the podium to speak.
"In defending itself, Israel is also defending many of the countries whose delegates just left this hall," Netanyahu said on Thursday.
"In fact, I want you to know that many of their leaders even thank us privately for taking out Iran's nukes."
When Netanyahu walked to the rostrum, a mix of cheers, boos and mass walkouts erupted.
"Order in the hall, please," General Assembly President Khalilur Rahman said repeatedly.
Netanyahu's remarks were aimed largely at the audience at home as the country prepares for elections on October 27.
Netanyahu reminded the assembly of the scale of the October 7, 2023, attack in which Hamas militants killed about 1200 people.
"This is equal to 40,000 innocent Americans slaughtered in less than 24 hours," he said, or 16 times the death count of the September 11, 2001, attacks on New York and the Pentagon.
Netanyahu said the attack left Israel with no choice but to hit Hamas hard.
Many governments have accused Israel of committing war crimes, and Netanyahu himself faces an arrest warrant by the International Criminal Court accusing him of crimes against humanity.
While the war in Iran has been inconclusive and caused havoc on the global economy, Netanyahu insisted he had made the right decision.
He thanked US President Donald Trump for taking decisive action against Iran, and predicted Iran's theocratic government would fall.
Trump made a similar assertion when the war began nearly seven months ago, but the Iranian government appears to remain firmly in charge.
Netanyahu also accused New York City mayor Zohran Mamdani of spreading lies about Israel and endangering Jewish New Yorkers with his criticism of the country's actions in Gaza.
Before the prime minister arrived in New York, Mamdani called him a "war criminal" and called for his arrest.
Netanyahu's address is the cornerstone of an abbreviated trip to the United States as Israel has grown increasingly isolated throughout the war in Gaza.
The war began on October 7, 2023, when Hamas-led militants attacked Israel, killing about 1200 people and kidnapping 251.
At least 73,922 Palestinians have been killed in Israel's subsequent offensive, according to the Gaza health ministry.
A ceasefire agreed to by Israel and Hamas in October 2025 halted the heaviest of the fighting and led to the release of the remaining hostages, yet further steps have since stalled.
Israel maintains control of most of Gaza and continues to carry out air strikes near military-held zones.
Hamas has not disarmed or relinquished power and there has been no progress towards reconstruction in the mostly destroyed territory.
Palestinian President Mahmoud Abbas also addressed the UN General Assembly on Thursday, delivering pre-recorded remarks after he was denied a US visa for the second year in a row.
Abbas urged the international community to take more tangible action against Israel.
"What, then, is the international community waiting for before it acts to protect the Palestinian people?" Abbas said.
