Senator Joe Manchin III, the conservative West Virginia Democrat, announced on Thursday that he would not seek re-election, dealing a blow to Democrats’ chances of holding the Senate.

Instead, Mr. Manchin, who was likely to face a strong Republican challenger to keep his Senate seat in a deeply red state, said he would continue exploring whether there was an appetite in the country for a centrist third-party bid for the presidency. That prospect has alarmed many Democrats who fear such a run could doom President Biden’s chances of holding the White House.

“After months of deliberation and long conversations with my family, I believe in my heart of hearts that I have accomplished what I set out to do for West Virginia,” Mr. Manchin said in a video news release. “I have made one of the toughest decisions of my life and decided that I will not be running for re-election to the United States Senate, but what I will be doing is traveling the country and speaking out to see if there is an interest in creating a movement to mobilize the middle and bring Americans together.”

The decision was an immediate setback for Democrats’ hopes of holding a majority in the Senate, where they currently control 51 votes — 48 Democrats and three independents. Mr. Manchin was seen as the only Democrat with a chance of holding the seat.

A recent poll showed Gov. Jim Justice, a Republican, as the front-runner in the race.

Behind closed doors, Senator Chuck Schumer, Democrat of New York and the majority leader, had been relentlessly encouraging Mr. Manchin to run again. At the same time, Democrats have been hoping that he would not pursue a presidential bid through the centrist political group No Labels, which they fear would draw votes from Mr. Biden and help elect a Republican.

“I know our country isn’t as divided as Washington wants us to believe,” Mr. Manchin said in his statement. “We share common values of family, freedom, democracy, dignity and a belief that together we can overcome any challenge. We need to take back America and not let this divisive hatred further pull us apart.”

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