On February 20, 2019, Byrne announced his candidacy for the 2020 United States Senate election in Alabama, challenging incumbent Democratic U.S. Senator Doug Jones. He accused Jones of not supporting "Alabama's interests and Alabama values" in his announcement speech. Byrne was defeated in the first round of the Republican primary; he won districts near Mobile but did poorly elsewhere in the state. Tommy Tuberville and Jeff Sessions advanced to the Republican primary runoff.
