The former Republican Nebraska senator was confirmed by 58-41.
Chuck Hagel will replace outgoing Defense Secretary Leon Panetta, who was confirmed by 100-0 in June 2011.
Two weeks ago, Republicans delayed a vote, questioning Chuck Hagel’s past positions on Israel and Iran, and his qualifications for the post.
But they dropped the filibuster stalling tactic, the first time it has ever been used to delay confirmation of a defense secretary, after a week-long recess.
President Barack Obama’s Democratic Party holds a 55-45 edge in the chamber, and Chuck Hagel ultimately only needed 51 votes to be confirmed.
Republican Senators Thad Cochran, Rand Paul, Richard Shelby and Mike Johanns voted in favor of Chuck Hagel’s appointment.
After the acrimonious nomination fight, President Barack Obama said he was pleased there had been at least some bipartisan support for Chuck Hagel.
“I am grateful to Chuck for reminding us that when it comes to our national defence, we are not Democrats or Republicans. We are Americans, and our greatest responsibility is the security of the American people,” said Barack Obama.
Earlier on Tuesday, Chuck Hagel, a decorated Vietnam veteran, passed a crucial procedural vote that needed the support of 60 senators.
Among the sticking points in Chuck Hagel’s nomination process was a remark he made in a 2008 book that the “Jewish lobby” intimidated decision-makers on Capitol Hill.
Republican senators also said they feared the 66-year-old Chuck Hagel would be too lax on Iran.
During his time as a senator, Chuck Hagel angered Republican party leaders when he pilloried former President George W Bush’s handling of the Iraq war.
Ted Cruz, an outspoken conservative first-term senator from Texas, recently suggested without evidence that Chuck Hagel had accepted payments from North Korea.
During his confirmation hearing in January, Chuck Hagel sought to reassure the Senate armed services committee that he was “fully committed” to preventing Iran from obtaining a nuclear weapon.
He also apologized for the “Jewish lobby” comment, saying he could not be defined by any single quote.
Chuck Hagel’s Democratic Party supporters produced other remarks and evidence they said showed he would stick to existing US policy on Israel and Iran.
The White House had warned of great risks in leaving the Pentagon without a leader at a time of budget challenges and while the US has troops in Afghanistan.
Senate Democrats blasted their colleagues for the blocking tactics, but some Republicans protested that they needed more time to weigh the nomination.
Others, including several senior Republicans on the armed services committee, said outright that they would not back Chuck Hagel.
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