Republican Missouri Attorney General Eric Schmitt won the open seat, defeating Democrat Trudy Busch Valentine.

[6] In the speech announcing his candidacy, Schmitt tied himself to Donald Trump and spoke against "the radical left".

[6] He pledged to vote against Mitch McConnell for the Senate Republican party leadership position.

[7] In February 2022, Hartzler's campaign released a 30-second ad criticizing Lia Thomas, a transgender swimmer on the University of Pennsylvania women's team.

"[10][9] Greitens was endorsed by former New York City mayor Rudy Giuliani, former U.S. Secretary of the Interior Ryan Zinke, and Fox News personality Kimberly Guilfoyle, the latter joining his campaign as a national chair.

[11] Many Republican officials, strategists, and donors maneuvered to stymie Greitens's attempted comeback, believing that the scandal surrounding his resignation as governor, his extramarital affair, and the sexual assault accusation against him would make him a weak general election candidate and lead to the loss of the Senate seat to a Democrat.

[18] Republican officials, including Rick Scott, waged a campaign to persuade Donald Trump not to endorse Greitens.