DeVos was born Elisabeth Prince on January 8, 1958. She grew up in Holland, Michigan, the daughter of Elsa (Zwiep) Prince (later, Broekhuizen) and Edgar Prince, a Billionaire industrialist. Both of her parents are of Dutch ancestry, and her family's original surname was "Prins". Edgar was the founder of Prince Corporation, an automobile parts supplier based in Holland, Michigan.

DeVos was educated at the Holland Christian High School, a private school located in her home town of Holland, Michigan. She graduated from Calvin College in Grand Rapids, Michigan, where she earned a Bachelor of Arts degree in Business economics in 1979. During college, DeVos was "involved with campus politics," according to Philanthropy magazine.

Since 1982, DeVos has participated in the Michigan Republican Party. She served as a local precinct delegate for the Michigan Republican Party, having been elected for 16 consecutive two-year terms since 1986. She was a Republican National Committeewoman for Michigan between 1992 and 1997, and served as chairwoman of the Michigan Republican Party from 1996 to 2000. In 2004, the Lansing State Journal described DeVos as "a political pit bull for most of [Gov. Jennifer] Granholm's 16 months in office," and said that if DeVos was not Granholm's "worst nightmare," she was "certainly her most persistent". Bill Ballenger, Editor of the newsletter Inside Michigan Politics and a former Republican state senator, called DeVos "a good behind-the-scenes organizer and a good fund raiser" as well as "a true believer in core Republican issues that leave nobody in doubt on where she stands". DeVos resigned the position in 2000. She said in 2000, "It is clear I have never been a rubber stamp... I have been a fighter for the grassroots, and following is admittedly not my strong suit." In 2003, DeVos ran again for party chairman and was elected to the post without opposition.

The Dick & Betsy DeVos Family Foundation was launched in 1989. The foundation's giving, according to its website, is motivated by faith, and "is centered in cultivating leadership, accelerating transformation and leveraging support in five areas", namely education, community, arts, justice, and leadership. In 2015, the DeVos Foundation made $11.6 million in charitable contributions, bringing the couple's lifetime charitable giving to $139 million. Forbes ranked the DeVos family No. 24 on its 2015 list of America's top givers.

During the 1990s, she served on the boards of Children First America and the American Education Reform Council, which sought to expand school choice through vouchers and tax credits. She and her husband worked for the successful passage of Michigan's first charter-school bill in 1993, and for the unsuccessful effort in 2000 to amend Michigan's constitution to allow tax-credit scholarships or vouchers. In response to that defeat, DeVos started a PAC, the Great Lakes Education Project, which championed charter schools. DeVos's husband and John Walton then founded All Children Matter, a political organization, which she chaired.

DeVos is a Republican known for her support for school choice, school voucher programs, and charter schools. She was Republican National Committeewoman for Michigan from 1992 to 1997 and served as chair of the Michigan Republican Party from 1996 to 2000, with reelection to the post in 2003. DeVos has been an advocate of the Detroit charter school system and she is a member of the board of the Foundation for Excellence in Education. She has served as chair of the board of the Alliance for School Choice and the Acton Institute and headed the All Children Matter PAC, which has received wide criticism for meddling in elections at the state level.

The DeVos family is one of Michigan's wealthiest. Betsy DeVos's husband, Richard Marvin "Dick" DeVos Jr., is a multi-billionaire heir to the Amway fortune who ran Amway's parent company, Alticor, from 1993 to 2002. Dick DeVos is a major donor to conservative political campaigns and social causes, and was the 2006 Republican nominee for Governor of Michigan. Dick's Father, Richard Marvin DeVos Sr., co-founded Amway and is also the owner of the Orlando Magic NBA basketball team. Richard DeVos was listed by Forbes in 2016 as having a net worth of $5.1 billion, making him America's 88th wealthiest individual.

The Atlantic noted that DeVos had indicated in a 1997 op-ed that she expects results from her political contributions. "My family is the largest single contributor of soft money to the national Republican Party. I have decided to stop taking offense at the suggestion that we are buying influence," she wrote. "Now I simply concede the point. They are right." She also stated in the op-ed, "We expect to foster a conservative governing philosophy consisting of limited government and respect for traditional American virtues…We expect a return on our investment; we expect a good and honest government. Furthermore, we expect the Republican Party to use the money to promote these policies and, yes, to win elections."

With respect to educational-focused donations, the foundation from 1999 to 2014 supported private Christian schools (at least $8.6 million), charter schools ($5.2 million), and public schools ($59,750). Specific donations included $2.39 million to the Grand Rapids Christian High School Association, $652,000 to the Ada Christian School, and $458,000 to Holland Christian Schools.

DeVos in 2001 listed education activism and reform efforts as a means to "advance God's Kingdom". In an interview that year, she also said that "changing the way we approach ... the system of education in the country ... really may have greater Kingdom gain in the long run".

When DeVos was appointed US Education Secretary, it was revealed that she was an elder at Mars Hill Bible Church. During her tenure, she reportedly donated $431,000 to the church between 2002 and 2004 and $453,349 to Flannel, Producer of the NOOMA video series.

DeVos was appointed by President George W. Bush to the board of Directors of the Kennedy Center for the Performing Arts in 2004, and served until 2010. While she was on the board, she and her husband funded a center to teach arts managers and boards of Directors how to fundraise and manage their cultural institutions. The couple donated $22.5 million in 2010 to continue the endeavor, which was given in the name of the DeVos Institute of Arts Management.

In 2009, Betsy DeVos's son Rick DeVos founded ArtPrize, an international art competition held in Grand Rapids, Michigan. As of 2016 approximately 16 percent of ArtPrize's $3.5 million annual budget was provided by various foundations run by the DeVos family, with the rest provided by other foundations and local and national businesses.

DeVos and her husband were producers for a Broadway run of the stage play Scandalous: The Life and Trials of Aimee Semple McPherson, in 2012, based on the life of the famous evangelist and featuring a book and lyrics written by Kathie Lee Gifford. The show ran for three weeks, closing in December 2012 after receiving negative reviews.

DeVos and Joel Klein said in a May 2013 op-ed that residents of Maine "are now given information on school performance using easy-to-understand report cards with the same A, B, C, D and F designations used in student grades". This system, they argued, "truly motivates parents and the community to get involved by simply taking information that education officials have had for years and presenting it in a way that is more easily understood."

DeVos has been an advocate for the Detroit charter school system. Douglas N. Harris, professor of economics at Tulane University, wrote in a 2016 New York Times op-ed that DeVos was partly responsible for "what even charter advocates acknowledge is the biggest school reform disaster in the country". In the National Assessment of Educational Progress, Detroit had the lowest reading and mathematics scores "by far" over any city participating in the evaluation. According to Harris, she designed a system with no oversight in which schools that do poorly can continue to enroll students.

In October 2017, DeVos revoked 72 guidance documents of the Office of Special Education and Rehabilitative Services which outlined the rights of disabled students under the Individuals with Disabilities Education Act and the Rehabilitation Act.

In January 2018, Devos said in a speech that the American Federation of Teachers (AFT) found that "60 percent of its teachers reported having moderate to no influence over the content and skills taught in their own classrooms." In response, AFT noted that in the same survey of around 5000 educators, 86% felt that Devos had disrespected them.