Governor, Mayes played a notable role in the controversy surrounding the Daughters of the Republic of Texas' custodianship of the Alamo Mission in San Antonio, siding with Clara Driscoll over Adina De Zavala to demolish most of the remaining portions of the site's long barracks.

Historians Burroughs, Tomlinson, Stanford, in "Forget the Alamo" describe this event as the motivation for Clara Driscoll to found the Texas Historical Landmarks Association.

[17] However, Mayes declined, and immediately thereafter announced he was running for the office of Governor on a platform of statewide prohibition and local option.

[17] He was initially considered to be a favorite,[18] but withdrew after Thomas Ball consolidated prohibitionist support,[19] who in turn lost the nomination to James E. Ferguson.

The complaints against Mayes, who had been one of Ferguson's chief rivals for the 1914 Democratic gubernatorial nomination (he declined to run in favor of prohibitionist congressman Thomas Henry Ball), stemmed from negative editorials against Ferguson that the Brownwood Bulletin published while Mayes still owned half of the company.

[26] Later, Governor Ma Ferguson succeeded where her husband had not, and was able to remove funding for the School of Journalism entirely, effectively abolishing its programs.

His son William Harding Mayes Jr. was a print journalist who worked for the Brownwood Bulletin, was editor of the Ranger Times and Harlingen, Texas's The Valley Morning Star.

[35] He was later elected mayor of the Texas cities of Center (1925–1928)[36] and Brownwood (1939–1951),[37] where he owned and ran the KBWD radio station as part of a larger broadcasting chain.

[50] Their son, Wendell Wise Mayes Jr., was a prominent diabetes philanthropist and radio journalist who won a George Foster Peabody Award for broadcasting work he did on civil rights.