Mr Fetterman, who currently serves as Pennsylvania’s lieutenant governor, sprung to national prominence as one of the ex-president’s most vocal critics in the days after the 2020 election.
The 6ft 8in politician had widely been expected to run for the seat, having previously run for the Senate in 2016.
In 2005 Mr Fetterman was elected mayor of Braddock, Pennsylvania, where he still lives with his family in a converted Chevy car showroom.
“These places across Pennsylvania feel left behind, they don’t feel part of the conversation,” said Mr Fetterman, 51, in his announcement video.
“That’s why Donald Trump went to these small counties, and held these big rallies. We cannot afford to take any vote for granted.”
Mr Fetterman has been open about bringing back Mr Trump’s voters to the Democratic Party, while still supporting marijuana legalisation, expanded LGBTQ rights, and an increase to the minimum-wage.
“I’m going to fight not for one part of Pennsylvania, not for one party of Pennsylvania, but for one Pennsylvania,” he added in a statement.
“I’m running for the United States Senate for the same reason I ran for lieutenant governor in 2018 and mayor of Braddock 16 years ago, because I believe in a set of core truths.”
Mr Fetterman was a constant critic of the Trump campaign’s attempts to overturn his loss to Joe Biden in battleground states, of which Pennsylvania was one.
“If the President’s campaign doesn’t stop losing, the Cleveland Browns are gonna sue for trademark infringement,” he tweeted after a courtroom loss in the state.
He also mocked Mr Trump’s efforts by saying that “he can sue a ham sandwich” but it would not change Mr Biden’s win in the state.
And he said that the only problem with the election count was the “Trump campaign showing up on our corner in Philadelphia like some sad carnival barker, making outlandish claims.”
He described Republicans legal efforts to keep Mr Trump in power as a “big hot flaming pile of garbage” that would end in a “supernova of supreme humiliation.”