Holder also is the only African-American currently in President Barack Obama's Cabinet. He had strong bipartisan support in Monday's vote.
The chairman of the Senate Judiciary Committee, Sen. Patrick Leahy, called the vote historic. He noted that Holder's confirmation hearing was held while American was celebrating the 80th birthday Martin Luther King Jr.
Leahy said the confirmation would take the nation up the path that King wanted, where people are judged by the content of their character.
A small group of Republicans said they opposed Holder. They argued he was hostile to gun control and not fully supportive of the war on terrorism.
The debate over Holder's confirmation quickly turned partisan when his chief supporter denounced Republicans who sought a pledge not to prosecute intelligence agents who participated in harsh interrogations.
Leahy singled out Texas Republican John Cornyn as one who wanted to "turn a blind eye to possible lawbreaking before investigating whether it occurred."
Cornyn was one of the two no votes when Holder was approved for a full Senate vote 17-2 by the Judiciary Committee last week.
A small group of Republicans sought such a pledge from Holder, but he declined to give one. Leahy has been infuriated for several weeks by such demands.
"No one should be seeking to trade a vote for such a pledge," Leahy said.
Despite the partisan beginning, the ranking Republican on the Judiciary Committee, Arlen Specter of Pennsylvania, said Holder made mistakes but was well-qualified for the job and should be confirmed.
Holder's confirmation will trigger reviews - and changes - to the most controversial Bush administration policies, from interrogation tactics to terrorism trials and warrantless surveillance.
Those are some of the known issues. Even Holder doesn't know what he'll find when he looks at secret memos in the Justice Department Office of Legal Counsel.
As the nation's first African-American attorney general, Holder also will have to rehabilitate a department that under President George W. Bush was criticized for injecting politics in hiring career officials and firings of U.S. attorneys.
He'll have to decide whether to prosecute Justice Department officials who may have violated the law in some of these policies and tactics.
Holder also could reverse Bush's orders to former aides not to testify before Congress on their private advise discussions on the U.S. attorney firings.
To the satisfaction of Democrats and consternation of some Republicans, Holder told his confirmation hearing, "Waterboarding is torture." The statement about an interrogation technique that simulates drowning was an important signal of a policy change from Bush's view that the tactic was legal and not torture.
Obama issued an executive order to close the U.S. detention center at Guantanamo Bay, Cuba, within a year.
He also created a special task force, co-chaired by the attorney general and the secretary of defense, to review detainee policy going forward.
The group will consider policy options for apprehension, detention, trial, transfer or release of detainees and report to the president within 180 days.
One of Holder's most intriguing missions will be to review the Office of Legal Counsel, whose lawyers justified the use of controversial interrogation tactics and viewed themselves as attorneys for the White House.
The Justice Department's inspector general, in a report on the removal of nine U.S. attorneys, said the legal counsel's office - in effect - thumbed its nose at department internal investigators and refused to provide a crucial document. The office stated the White House counsel's office directed it not to provide the information.
Holder also said he would review why career prosecutors in Washington decided not to prosecute the former head of the department's Civil Rights Division.
An inspector general's report last month found that Bradley Schlozman, the former head of the division, misled lawmakers about whether he politicized hiring decisions.
The three former top aides to Bush - Karl Rove, Harriet Miers and Josh Bolten - have declined to testify about the U.S. attorney firings on orders from Bush while he still was in office. Rove and Miers at the time were former aides, raising the question of whether White House aides no longer in government could be compelled to testify.
If Obama reverses Bush's policy, it would create a new legal issue: whether a former president's order against testifying would still be valid.
Holder also will likely review civil liberties issues including warrantless surveillance.
After a lengthy and heated debate that pitted privacy and civil liberties concerns against the desire to prevent terrorist attacks, Congress last year eased the rules under which the government could wiretap American phone and computer lines to listen for terrorists and spies.
Holder said he would reexamine a ruling by former Attorney General Michael Mukasey that immigrants facing deportation do not have a right to government-provided lawyers.
Holder said he understands the desire to expedite immigration court proceedings, but the Constitution also requires that proceedings be fair.