The confirmation means President Donald Trump will now have five of his 15 cabinet members in place more then two weeks into his administration, along with the CIA director and US ambassador to the United Nations, which are cabinet-rank positions.
The chamber deadlocked at 50-50, with two Republicans breaking ranks to oppose DeVos, a champion of using taxpayer monies to help fund privately run schools.
"The Senate being equally divided, the vice president votes in the affirmative, and the nomination is confirmed," Pence said.
It was the first time a sitting vice president has voted to break a tie for a cabinet pick.
Afterward, Pence tweeted that the confirmation was "a vote for every child having a chance at a world-class education."
Contentious pick
Her nomination has proven to be the most contentious of Trump's picks.
Pence's vote was needed to save DeVos, who had triggered an outpouring of frustration and anger when Trump nominated the 59-year-old political scion from Michigan late last year.
Two moderate Senate Republicans, Susan Collins and Lisa Murkowski, bucked Trump and opposed his pick, citing her lack of qualifications for the post that oversees thousands of schools, millions of school children and curriculum standards.
Democrats were unable to convince another Republican to defect despite intense lobbying efforts that culminated with an all-night Democratic talk-a-thon late Monday into Tuesday on the Senate floor.
Senator Patty Murray said DeVos's performance at last month's confirmation hearing "underscored how unprepared she is to serve as secretary of education."
Murray, a former pre-school teacher, added: "There are open questions about her financial entanglements... and lack of understanding about basic education issues."
DeVos, a former chair of the Michigan Republican Party, never attended public school or worked in the public school system.
Supporters praise the businesswoman and philanthropist as a fierce advocate of school choice, a US movement that seeks to use tax credits and vouchers to allow parents to opt out of the public school system in favor of privately managed charter schools for their children.
Attorney general nominee next
Republican Senator Rob Portman said DeVos would not rule with a heavy hand from Washington.
"She strongly supports local control of education and has pledged not to impose her own views on states and local school districts, but rather to allow them -- along with parents -- to make the decisions that best fit the needs of their children," Portman said.
Trump rallied Republicans with a pre-vote tweet: "Senate Dems protest to keep the failed status quo. Betsy DeVos is a reformer, and she is going to be a great Education Sec. for our kids!"
The president has strongly criticized Democrats for opposing his cabinet nominations, saying they should be "ashamed of themselves" for slow-walking the process.
One nominee that Democrats have pushed back sharply against is one of the Senate's own, US attorney general nominee Senator Jeff Sessions, an early Trump backer during the presidential campaign.
Sessions endured a contentious hearing, during which Democrats questioned his civil rights record and his opposition to immigration.
But on Tuesday, his colleagues voted to advance his nomination, setting up a confirmation vote likely for later this week.
DeVos is less well known than Sessions. But she is a fixture in the education world, having served on the boards of not-for-profit groups that support school choice.
"Parents no longer believe that a one-size-fits-all model of learning meets the needs of every child, and they know other options exist -- whether magnet, virtual, charter, home, religious, or any combination thereof," she said at her confirmation hearing.
Devout Christian beliefs are a hallmark of the DeVos clan, and Betsy has fought hard to carve out broader space for religion in the education world.
Until her nomination she chaired the American Federation for Children, the DeVos family's umbrella organization that supports advancement of school choice outside of Michigan.
"Our work in Michigan was so successful that some of our friends in the movement began to say, 'We really need to do this nationally,'" DeVos said in a 2013 interview with the Philanthropy Roundtable.
"And I said, 'Yes, I think we do.'"
