"If Israel is forced to stand alone, Israel will stand alone," Netanyahu said.
Speaking at a Holocaust Remembrance Day ceremony at the Yad Vashem memorial in Jerusalem, he lamented that when the Nazis killed six million Jews during World War II, his people "were totally defenceless against those who sought our destruction.
"No nation came to our aid," he said as the Israeli flag billowed at half mast and survivors of the Holocaust prepared to light torches.
"Today, we again confront enemies bent on our destruction," Netanyahu told the large crowd gathered for the ceremony.
One yellow chair sat empty representing the hostages still held captive by Hamas in Gaza.
"I say to the leaders of the world, no amount of pressure, no decision by any international forum, will stop Israel from defending itself."
He lamented the surge of criticism seen around the world against Israel over its war in Gaza, ignited after Hamas's unprecedented October 7 attack.
And he denounced "this terrible volcano of anti-Semitism" that he said was surging around the world.
Netanyahu also compared the protests seen at universities across the United States and around the world to the discrimination against Jews at German universities during World War II.
"What a distortion of justice and history," he said.
The criticism, he said, was not "due to the actions that we do, but because we exist... because we are Jews.
"You will not chain our hands... Israel will continue to fight human evil... until victory," he said.
"We will defeat our genocidal enemies. Never again is now!"
Gaza's bloodiest-ever war began following Hamas's attack on Israel that resulted in the deaths of more than 1,170 people, mostly civilians, according to an AFP tally of Israeli official figures.
Militants also seized some 250 hostages during the attack. Israel estimates 128 are still held captive in Gaza, including 35 the army says are dead.
Vowing to destroy Hamas, Israel's retaliatory offensive has killed at least 34,683 people in Gaza, mostly women and children, according to the Hamas-run territory's health ministry.
