Neil Bremer (Ted Danson) is a wealthy businessman who runs for mayor of Los Angeles "for all the wrong reasons." Once he wins he has to figure out what he stands for, gain the respect of his staff, and connect with his teenage daughter, all while controlling the coyote population.

On July 18, 2019, it was reported that NBC had given a 13-episode straight-to-series order to an untitled Tina Fey and Robert Carlock comedy starring Ted Danson, who is set to play a wealthy businessman running for mayor of Los Angeles. Originally meant to be a spin-off/continuation of Fey's series 30 Rock, the series was to star Alec Baldwin reprising his 30 Rock role of Jack Donaghy, following his political career in New York City. After around a year of negotiations, Baldwin dropped out of the project and was replaced with Danson. Danson refused to move from Los Angeles to New York, so the series was rewritten to take place there.

On May 11, 2020, it was announced that the series would be called Mr. Mayor. The series would be executive produced by Tina Fey, Jeff Richmond, Robert Carlock and David Miner. Production companies involved with the series include Little Stranger, Bevel Gears, 3 Arts Entertainment and Universal Television. A first-look tease of the series was included as an end tag on the Peacock stream of "30 Rock: A One-Time Special" uploaded on July 16, 2020. The first season began airing on NBC on January 7, 2021, and concluded after nine episodes on February 25, 2021. On March 22, 2021, the series was renewed for a second season, which premiered on March 15, 2022 and ended on May 17, 2022. On May 12, 2022, NBC canceled the series after two seasons.
In 2019, Deadline reported Bobby Moynihan had joined the cast as Jayden and later that Holly Hunter had also joined the cast as Arpi. In early 2020 Vella Lovell joined the cast as Mikaela, Mike Cabellon joined the cast as Tommy, and Kyla Kenedy joined the cast as Orly Bremer.
On March 12, 2020, Universal Television suspended the production of the series amid the emergence of COVID-19 in the United States. Filming for the first season commenced shortly after, but was put on hold once again on December 14, 2020, after several crew members tested positive for COVID-19. The following day, it was reported that production would be suspended for the rest of 2020 and was scheduled to resume in January 2021. However, filming for the first season did not resume and the season was cut four episodes short due to the pandemic.

The first season of the show premiered on NBC with two episodes on January 7, 2021. In July 2020, an end tag of "30 Rock: A One Time Special" on its post-broadcast stream on Peacock included a teaser trailer of the series and later that year in November 2020, a trailer was released. The nine-episode season concluded with the episode "#PalmTreeReform" on February 25, 2021. The series was acquired by Citytv in Canada. A holiday special episode titled "Mr. Mayor's Magical L.A. Christmas" aired on December 15, 2021, as the second season premiere, ahead of the second season time slot premiere which is March 15, 2022.