"The world needs to hear unequivocally from you that Israel - our friend, ally, and strategic partner - is not alone in facing these threats," 14 lawmakers said in a letter released as Obama arrived in New York.
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The senators accused Turkish Prime Minister Recep Tayyip Erdogan of "anti-Israeli rhetoric," the attack on the Israeli embassy in Cairo, and the Palestinians' push to raise their status at the world body.
"We believe it is imperative for you to speak strongly, forthrightly and publicly about US concerns over these developments," they wrote to the president, who was to address the UN General Assembly.
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"We need to make it clear that we will not tolerate continued threats to Israel by governments or individuals in the region or attempts to delegitimize Israel at the UN or other international forums. Violence and unilateralism against Israel will be met with the strongest US opposition," they said.
Democratic Senators Robert Menendez, Bob Casey, Kirsten Gillibrand, Dick Blumenthal, Ben Cardin, Chuck Schumer, and Chris Coons, Republican Senators Jon Kyl, Susan Collins, Mark Kirk, Orrin Hatch, Marco Rubio, and Johnny Isakson, as well as Independent Senator Joe Lieberman signed the letter.
The lawmakers warned "political and physical attacks on Israel" raised "the possibility of a region-wide deterioration into violence" and that "Israel's real sense of growing isolation will make it much more difficult to move the Mideast in a positive direction."
Meanwhile, Republican presidential candidate Michele Bachmann slammed Obama over his foreign policy.
"I don't believe Israel should have to give away any more of its land," she told CNN Monday. "The president hasn't done Israel any favors."
Instead, she advised the president to "disallow" Iranian president Mahmoud Ahmadinejad from stepping "one foot" in the US for his persistent threats against Israel. "He is a genocidal madman," Bachmann said.
Texas Governor Rick Perry is slated to meet Deputy Foreign Minister Daniel Ayalon as well as Jewish leaders on Tuesday. Former Massachusetts Governor Mitt Romney will also be arriving in New York in the backdrop of the General Assembly meeting.