"I've always said this Brett, if I can't go home and explain to the people of West Virginia I can't vote for and I cannot vote to continue with this piece of legislation. I just can't," Manchin, a key centrist, said on "Fox News Sunday" to host Brett Bair.
"I've tried everything humanly possible. I can't get there," he said.
Last week, Biden all but confirmed that Senate Democrats are unlikely to vote on the House-passed $1.7 trillion social spending package before Christmas, a self-imposed deadline. In a statement, Biden said he had "a productive call" with House Speaker Nancy Pelosi, D-Calif., and Senate Majority Leader Chuck Schumer, D-N.Y. earlier in the day Thursday after meeting with Manchin, but also emphasized the lengthy negotiating process that lies ahead.
Manchin on Sunday said, "This is a no on this legislation."
"I have tried everything I know to do and the president has worked diligently. He's been wonderful to work with. He knows I've had concerns and the problems I've had," he added.
Manchin, a linchpin of the 50-50 Senate, lashed out at reporters last week when pressed on his concerns with the legislation, such as the inclusion of child tax credit payments, which are set to expire at the end of the year.
Democrats have shaped much of the current version of the bill around the demands of Manchin, who represents a ruby-red state that Biden lost by 39 points last year. If he bolts, the package collapses.
This story first appeared on NBCNews.com.