Mayes Middleton and his wife, Macy, have four children.  Mayes is President of Middleton Oil Company, an independent oil and gas company, and also runs ranching, cattle, and farming operations. He and his wife support numerous local community organizations and faith-based charities. Mayes was first elected to the Texas House of Representatives in 2018 to represent House District 23, encompassing Chambers County and part of Galveston County. Representative Middleton serves on the House Committees on Insurance, Judiciary & Civil Jurisprudence, and Local & Consent Calendars.

Mayes has consistently ranked as one of the top 10 most conservative members of the Texas House in his two sessions in the Legislature, and is also Chairman of the Texas House Freedom Caucus.