Donald Trump's nomination of school choice activist Betsy DeVos as education secretary is on thin ice after two Republican senators vowed to vote against her.

DeVos, a billionaire Republican donor who spent more than two decades promoting charter schools, has emerged as one of Trump's most controversial cabinet picks facing fierce opposition from Democrats, teachers unions and civil rights activists. With senators Susan Collins of Maine and Lisa Murkowski of Alaska in opposition, the nomination could die if DeVos loses the support of one more Republican — and all Democrats vote against her.

Murkowski said she believed DeVos has much to learn about public education.

"I have serious concerns about a nominee to be secretary of education who has been so involved on 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," Murkowski said.

If all other Republican senators support DeVos, and all Democrats oppose her, she would end up with a 50-50 vote in the Senate and Vice-President Mike Pence would have to break the tie to confirm her. A vote is expected in the coming days.

Senator Lamar Alexander of Tennessee, the Republican chairman of the health, education, labour and pensions committee, praised DeVos and expressed confidence that she would be confirmed.

"Mrs. DeVos believes in our children, their teachers and parents — she believes in the local school board instead of the national school board," Alexander said in a statement. "She's committed to public education, and there's no better example of that than her work on the most important reform of public schools in the last 30 years — public charter schools."

White House press secretary Sean Spicer said he wasn't concerned about the defections by Collins and Murkowski.

"I have 100 per cent confidence she will be the next secretary of education. She is an unbelievably qualified educator and advocate for students, teachers, parents," he said after the two senators announced their opposition.

Democrats have vigorously opposed DeVos, questioning her commitment to public education, her overall qualifications to lead the Education Department and her views on LGBT rights, the needs of students with disabilities and potential conflicts of interest arising from her business holdings.

Randi Weingarten, president of the American Federation of Teachers, expressed hope Wednesday that other Republicans would also reconsider their support for DeVos.

"The more people get to know how ill-equipped Betsy DeVos is to strengthen public schools, how disconnected she is from public schools, and how her record is focused on pursuing for-profit charters and vouchers and not on helping children, the more the people who believe in the importance of public education are joining to oppose her," Weingarten said.

DeVos, 59, is the wife of Dick DeVos, the heir to the Amway marketing fortune. She has spent more than two decades advocating for charter schools in her home state of Michigan, as well as promoting conservative religious values.