Obama's nominee, Republican former senator Chuck Hagel, has faced intense opposition by current lawmakers and was grilled by the likes of Senator John McCain during a testy hearing in which critics questioned Hagel's positions on Iran, nuclear weapons, Israel and the US troop surge in Iraq.
"Senator Hagel's performance at his confirmation hearing was deeply concerning, leading to serious doubts about his basic competence to meet the substantial demands of the office," the senators, led by number two Republican John Cornyn, said in a letter to Obama.
"While senator Hagel's erratic record and myriad conversions on key national security issues are troubling enough, his statements regarding Iran were disconcerting."
Hagel stumbled at times during his lengthy testimony late last month, mistakenly saying he favored "containment" of Iran instead of Obama's policy of preventing Tehran from obtaining nuclear weapons. He corrected himself later after being handed a note.
"If senator Hagel becomes secretary of defense the military option (against Iran) will have zero credibility," the senators wrote, adding that Hagel lacked the "broad-based bipartisan support" enjoyed by outgoing chief Leon Panetta that they said is critical to the success of the next Pentagon head.
Republicans managed to force a delay on Hagel's confirmation vote last week, saying some colleagues need more time to study Hagel's finances and speech transcripts.
White House spokesman Jay Carney insisted Hagel would "absolutely not" withdraw his name.
Delaying the confirmation, Carney said, would hobble the Defense Department's readiness during a period of rising Middle East tensions, and amid the challenges of winding down the war in Afghanistan and the continuing nuclear threat from North Korea.
"We need our new secretary of defense on the job to be part of the significant decisions that have to be made as we bring that war (in Afghanistan) to a responsible end," he said.
A vote is expected Tuesday in the Democratic-held Senate, and some Republicans foresee Hagel's confirmation.
McCain said on Sunday that he was "confident" Hagel would have the necessary votes, although he does not support him.
Hagel got a boost Thursday when a spokesman for Senator Richard Shelby said that "barring any unforeseen surprises" the Alabama Republican would support Hagel's nomination.