WASHINGTON — Senator Joe Manchin III, Democrat of West Virginia, said on Sunday that he could not support President Biden’s signature $2.2 trillion social safety net, climate and tax bill, all but dooming his party’s drive to pass the measure as written.

“I cannot vote to continue with this piece of legislation,” Mr. Manchin said on “Fox News Sunday,” citing concerns about adding to the national debt. “I’ve tried everything humanly possible. I can’t get there. This is a no.”

The comments from Mr. Manchin, a crucial Democratic holdout, dealt the latest, perhaps fatal blow to the centerpiece of Mr. Biden’s domestic agenda. With Republicans united in opposing the legislation, Democrats needed to secure the vote of every senator in their party for the measure to pass an evenly divided Senate.

For months, Mr. Manchin had huddled privately with Mr. Biden and his top officials in an attempt to secu re a compromise that the West Virginia Democrat could support. His objections forced the White House to substantially curtail the scope of the package and remove certain programs, including the creation of a clean electricity program and a plan to ban new oil drilling off the Atlantic and Pacific coasts.

As early as last week, even as Mr. Biden confirmed that efforts to pass the legislation had stalled, he waxed optimistic, saying that talks with Mr. Manchin would continue and that he believed that “we will bridge our differences and advance the Build Back Better plan.”

The Senate left for the holidays this week without completing work on the sprawling package, vowing to continue work once senators reconvene in early January. But Mr. Manchin on Sunday appeared to close the door on further substantive talks, complaining that his colleagues had been spending months on employing tricks to make the legislation appear less costly rather than truly paring it down.

“They’re just trying to make the adjustment for the time to fit the money or the money to fit the time,” Mr. Manchin said. “Not changing our approach, not targeting things we should be doing.”

His comments are sure to infuriate his Democratic colleagues, who had hoped to pass the legislation before the end of the year. It remains to be seen whether they will respond by significantly modifying the bill in the hopes of salvaging something that can pass.

“I think he’s going to have a lot of explaining to do to the people of West Virginia,” said Senator Bernie Sanders, the Vermont independent who heads the Senate Budget Committee, calling for a vote on the Senate floor on the legislation despite Mr. Manchin’s comments.

“We’ve been dealing with Mr. Manchin for month after month after month,” he added, speaking on CNN’s “State of the Union.” “But if he doesn’t have the courage to do the right thing for the working families of West Virginia and America, let him vote no in front of the whole world.”

Chris Cameron contributed reporting.