WASHINGTON — Two Republican senators on Wednesday said they would vote against President Trump’s nominee for education secretary, delivering a blow to the White House and raising the possibility that Vice President Mike Pence would have to break a tie to win her confirmation.

The nominee, Betsy DeVos, a billionaire with a complex web of financial investments, had already faced fierce opposition from Democrats and labor unions because of her political contributions to Republicans and her involvement in pushing alternatives to public education. But her confirmation hearing in front of the Senate Committee on Health, Education, Labor and Pensions, during which she flubbed answers on education policy, also brought concerns from Republicans.

Senator Lisa Murkowski, Republican of Alaska, said Ms. DeVos had failed to demonstrate that she understood what public schools needed to succeed. “I have serious concerns about a nominee to be secretary of education who has been so involved in one side of the equation, so immersed in the push for vouchers, that she may be unaware of what actually is successful within the public schools, and also what is broken and how to fix them,” Ms. Murkowski said.

Senator Susan Collins, Republican of Maine, said she respected Ms. DeVos’s clear devotion to students and “valuable work” in education. But she said she remained troubled by Ms. DeVos’s focus on alternatives to public education, as well as what Ms. Collins called a “lack of familiarity” with federal laws protecting children with special needs and disabilities.