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Mr Netanyahu will hold meetings with leaders including US President Joe Biden, who has so far denied him an official invitation to the White House.
The move is unprecedented in the history of US-Israel relations and widely viewed as a signal of the Biden administration’s disapproval of Israel’s right-wing government.
The two leaders' meeting, scheduled for Wednesday, will take place during the UNGA.
Before he left Israel, Mr Netanyahu said his meeting with the US President would “first and foremost [discuss] Iran and expanding the circle of peace”.
“Today, the world is seeing that Iran is violating all of its commitments, that it brazenly lies, and that it intends both to develop nuclear weapons and continue its aggression in the region,” Mr Netanyahu said.
“This regime needs to know that we will respond forcefully to any attack on our people and our citizens.”
Relations between Israel and Iran have been strained since the Islamic Revolution in 1979.
Iran is regarded as having sway over proxy forces in neighbouring countries and a holding a growing influence in Palestine.
Mr Netanyahu is also scheduled to meet billionaire entrepreneur Elon Musk, whose X social media platform, formerly known as Twitter, has come under mounting criticism for amplifying anti-Semitism in recent months.
Before his departure, Mr Netanyahu did not allude to any discussions of combating anti-Semitism, saying instead he would “discuss artificial intelligence [and] also work towards encouraging [Mr Musk] to invest in Israel in the coming years”.
“He is, to a large degree, paving the way that will change the face of humanity and also the face of the state of Israel,” he added.
“Israel needs to be a leader in artificial intelligence.
“Just as we turned it into a leader in cyber, so we will do in this field as well."
Anti-Netanyahu activists in San Francisco, where the meeting is scheduled, are organising a demonstration. The group named UnXeptable consists of American Israelis and Israelis who live in the city. Protests are expected to follow Mr Netanyahu throughout his visit.
The Israeli government’s plan to significantly reduce the power of the judiciary has drawn weekly mass protests in the past eight months, including demonstrations abroad.
Critics of the move say the proposals will end democracy in Israel. Advocates say the reforms are vital to reining in a powerful judicial system that has too much influence over elected politicians.