The vote, which was among senators' final business before a month-long recess, divided largely along party lines with 63 senators endorsing President Obama's second court pick and 37 opposed.
Kagan watched the televised vote with her colleagues at the Justice Department, while Obama received word of the confirmation in Chicago, where he has spent the past two days.
"Today's vote wasn't just an affirmation of Elena's intellect and accomplishments. It was also an affirmation of her character and her temperament; her open-mindedness and even-handedness; her determination to hear all sides of every story and consider all possible arguments," the president said after the vote.
Kagan's ascension to the bench is expected to preserve the court's ideological balance following liberal Justice John Paul Stevens' retirement. It also marks the first time three female justices will sit on the high court at the same time.
Nearly all Republicans and one Democrat, Nebraska Sen. Ben Nelson, opposed Kagan, who had been the Obama administration's solicitor general. Nelson is the first to break with his party on an Obama Supreme Court pick.
All Democrats and nine Republicans voted for Justice Sonia Sotomayor.
Republicans sought to cast Kagan as a political activist with insufficient legal or judicial experience to serve on the nation's highest court. They also targeted her decision as dean of Harvard Law School to bar military recruiters from the campus career center because of opposition to the "don't ask, don't tell" policy.
Some Republican leaders and conservative interest groups also warned lawmakers over Kagan's anti-gun, pro-abortion views.
"Be careful about it, because I'm afraid that we have a dangerous, progressive, political-type nominee," said Alabama Sen. Jeff Sessions in a floor speech last week. "I don't think the American people are going to hold harmless those who vote to impose a legal progressive, activist legislator from the bench upon them."
But Democrats, who have been concerned about conservative "activism" from the bench, say Kagan will be a mainstream, moderate voice on controversial topics such as campaign finance reform and employment discrimination.
"She gives balance to the court. I think she'll follow in the best traditions of Justice Stephens," said Maryland Democrat Sen. Ben Cardin on "Top Line." "I think she'll bring the type of leadership on the Supreme Court that will help ordinary Americans with their fight against big government and special interests."
Majority of Americans Backed Kagan
While Kagan does not have any judicial experience, her supporters have lauded her record outside the courtroom as solicitor general for the Obama administration, former dean of Harvard Law School and a staff attorney in the Clinton administration.
"Ms. Kagan's remarkable legal and academic career demonstrates her intellectual capacity to serve on the court," said Maine Republican Sen. Susan Collins. "Her writings, testimony, and my discussions with her all demonstrate not only a sweeping knowledge of the law, but also a love for the law, a passion for judicial reasoning."
The latest ABC News/Washington Post poll finds a 53 percent majority of Americans support Kagan's nomination – a similar level of support shown for previous successful nominees. Twenty-two percent said they had no opinion, up four points from a month earlier.
Kagan, 50, will formally become the Supreme Court's 100th associate justice when she is sworn in by Chief Justice John Roberts during a ceremony on Saturday afternoon.
ABC News' Ann Compton and Ariane de Vogue contributed to this report.