Kevin Faulconer, 46, is a two-term city councilman who is being forced from office due to term limits. The former public relations executive is a Republican.
Republican, civic and business leaders have endorsed Faulconer's bid.
The mayoral election will be held on November 19 to replace Bob Filner, who resigned in disgrace after multiple accusations of harassment from a host of women.
The current interim mayor, Todd Gloria, a Democrat, said Tuesday he would not run for the office.
Republican Carl DeMaio, who had previously run for mayor and was narrowly defeated by Filner, also said Tuesday he would not seek the office of mayor, and would continue to run for Congress.
City elections are nonpartisan, but party affiliation and endorsements bring money and organizational muscle. Democrats have a 13-point lead in voter registration, and Filner was the first Democrat to lead the city in 20 years and only the second in four decades.
If no candidate wins a majority - a good possibility with more than a dozen candidates in the race - the top two finishers will advance to a runoff.
Faulconer supported a ballot measure to cut pensions for city workers and wants to put more city services up for bid, but he has struck a more centrist tone than DeMaio did against Filner.
The most prominent Democrat in the race is Nathan Fletcher, a former state assemblyman and Marine combat veteran in Iraq. Now an executive at wireless technology titan Qualcomm Inc., he switched from Republican to independent just before finishing a strong third in last year's mayoral primary. He became a Democrat in May.
The filing deadline to run is Sept. 20.
The Associated Press contributed to this report.