"Candidates for president who think the United States can outsource Middle East security to dictators, or that America no longer has vital national interests at stake in this region are dangerously wrong," Clinton said at the American-Israel Public Affairs Committee (AIPAC) conference.
"It would be a serious mistake for the US to abandon our responsibilities, or cede the mantle of leadership for global peace and security to anyone else," Clinton said at the annual mega show of the powerful Israeli-American community.
Clinton's comments before thousands of Jewish voters were seen by many as a direct critique of the "policy of neutrality" advocated by Republican frontrunner Donald Trump.
Trump has vowed to be "neutral" in negotiations between Israelis and Palestinians, a significant break from the long-standing US foreign policy favouring Israel.
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During a debate in December, the billionaire real estate tycoon called the Israel-Palestinian relationship "the toughest negotiation there probably is of any kind."
"Tonight you'll hear from candidates with very different visions of American leadership in the region and around the world. You'll get a glimpse of a potential US foreign policy that would insult our allies, not engage them, and embolden our adversaries, not defeat them," she said.
"For the security of Israel and the world, we need America to remain a respected global leader, committed to defending and advancing the international order. An America able to block efforts to isolate or attack Israel. The alternative is unthinkable," she said.
"Israel's security is non-negotiable. America can't ever be neutral when it comes to Israel's security or survival. We can't be neutral when rockets rain down on residential neighborhoods, when civilians are stabbed in the street, when suicide bombers target the innocent. Some things aren't negotiable," Clinton said.
"Anyone who doesn't understand that has no business being our president," she said.
Clinton underlined the importance of "electing a president with a deep personal commitment to Israel's future.