The address has caused an uproar that has exposed tensions between Israel and its most important ally, the United States.
In accepting a Republican invitation to address Congress, Netanyahu angered the White House, which was not consulted with in advance of the invite, as well as Democrats who were forced to choose between showing support for Israel and backing their president.
Netanyahu plans to express his disapproval over a potential deal between Iran and world powers that he says falls short of preventing Tehran from having the ability to make an atomic bomb. A preliminary deadline is late this month.
"I feel deep and genuine concern for the security of all the people of Israel," Netanyahu told reporters on the tarmac, his wife by his side, before boarding his flight. "I will do everything in my ability to secure our future."
He called the trip a "crucial and even historic mission" and said he feels like "an emissary" of all citizens of Israel and the Jewish people.
Tuesday's speech to Congress has touched off a wave of criticism in Israel, where Netanyahu is seeking re-election on March 17.
His main challenger, Isaac Herzog, had demanded he cancel the speech. The former head of Israel's Mossad spy agency has called the address pointless and counterproductive. Netanyahu has long been a vocal critic of Iran, and his position is already well-known.
Stopping Iran from building a nuclear bomb has become a defining challenge for both President Barack Obama and Netanyahu, yet they have approached the issue differently.
Netanyahu considers unacceptable any deal that doesn't end Iran's nuclear programme entirely. Obama appears to be willing to leave some nuclear activity intact, backed by safeguards that Iran is not trying to develop a weapon.
Iran says its nuclear programme is for peaceful purposes.
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