Two GOP senators — Susan Collins of Maine and Lisa Murkowski of Alaska — announced Wednesday they will oppose Betsy DeVos’ nomination to be education secretary.

They are the first Republicans to break with President Trump on any of his Cabinet picks, and their defections could make it difficult for DeVos to win Senate confirmation.

“I simply cannot support her confirmation,” Collins said from the Senate floor.

If all of the Senate’s Democrats vote against DeVos, she would have 50 votes if all remaining Republicans backed her.

DeVos would then require the likely support of Vice President Mike Pence to break a tie and usher her into office.

Moderate Democrats who have previously supported Trump nominees — Sens. Joe Manchin (D-W.Va.) and Heidi Heitkamp (D-ND) — have already announced they’ll vote “no” on DeVos and say she’s unqualified for the post.

“Betsy DeVos has never attended or worked in a public school,” Manchin said in a statement.

“The needs facing rural schools in West Virginia are unique and her lack of exposure to public education is very concerning for me.”

DeVos, a former chairwoman of the Michigan Republican Party and mega ­donor to the GOP, has been a longtime champion of charter schools and private-school vouchers.

In 2010 she launched the American Federation of Children, a leading school-choice advocacy group.

Trump picked DeVos to reform the department, break up the bureaucracy and deliver school choice to all families.

Compared to other Trump nominees, DeVos’ confirmation hearing was rocky. She stumbled under questioning on federal disability-education law and said guns might be needed in some rural schools to defend against “potential grizzlies.”

White House press secretary Sean Spicer said Wednesday he has “zero” concern that there will be other GOP defections on ­Devos’ nomination.

“I am 100 percent confident she’ll be the next secretary of education,” Spicer told reporters at the daily White house press briefing.

“She is unbelievably qualified,” he added.

Spicer blasted Democratic efforts to block her nomination.

“I think the games that are being played with Betsy DeVos are sad,” he said.

As of now, DeVos may need the vote of Sen. Jeff Sessions (R-Ala.) to salvage her post.

Senate Majority Leader Mitch McConnell successfully moved late afternoon Wednesday to put DeVos up next in the queue for confirmation. A final vote could take place by next week.

Sessions is slated to leave the Senate as soon his colleagues confirm him as attorney general, which has now been delayed until DeVos is in the clear.