He became an active member of the American Farm Bureau Federation and served in multiple positions in the organization from the county to statewide level both before and after his terms in elected office.

Mixson entered politics in 1966, with an unsuccessful run in the Democratic primary election for a seat in the Florida Senate.

In 1978, Bob Graham, a state senator from South Florida, tapped Mixson to be his running mate to balance the ticket in his campaign for governor.

Mixson considered running for governor to replace Graham in 1986, but ultimately decided to retire from electoral politics and Republican Bob Martinez won the office.

[12][13][14] In 1965, E. H. Finlayson, president of the Florida Farm Bureau, announced that he would not seek reelection, and Mixson ran to succeed him, but later withdrew.

[25] In the primary he defeated incumbent Representative Coy J. Mitchell and later faced no opposition in the general election.

[30][31] In the Democratic primary he defeated John Grace, a 26 year old veteran of the Vietnam War, and in the general election Mixson faced no opposition.

[35] During the 1967–1968 session of the House of Representatives Mixson served on the Ad Valorem Taxation, Appropriations, Claims, Public Health and Welfare, and State Institutions committees.

[44] In 1973, an impeachment inquiry was held for Lieutenant Governor Thomas Burton Adams Jr. for using public employees for personal financial gain during his service as Secretary of Commerce.

[56] Following his selection he was endorsed by the Jackson County Floridian, the daily newspaper in Marianna, Florida, where Mixson lived, and by Guy Long, president of the NAACP in Jackson County, who held a press conference to refute rumors of Mixson being a redneck racist.

[66] On January 22, Mixson led a 37-member delegation, as Governor Graham was unable, to Guatemala City, Guatemala, for the state's fourth trade mission called the "Intercambio Comercial", with the past three being to Nicaragua, the Dominican Republic, and Venezuela, meant to increase trade between Florida and Central and South America.

[70] At the state Democratic convention Mixson was selected to serve as a delegate to the Democratic National Convention in support of Carter alongside Graham, James C. Smith, Doyle Conner, Claude Pepper, Hazel Talley Evans, and Phyllis Miller.

[71] From February 10 to 16, 1980, Mixson was meant to lead a 35-member delegation, which included Agriculture Commissioner Doyle Conner, state House Speaker J. Hyatt Brown, and Commerce Secretary Sidney Levin, during Florida's fifth Intercambio Comercial to Quito and Guayaquil, Ecuador.

[74][75] In April 1980, Mixson was criticized for his intervening to prevent the suspension of Marianna Circuit Court Clerk Raymond Bruner.

[76] On June 27, Graham signed an executive order to suspend Bruner with the order stating that "these women were subjected to improper sexual advances in actual physical form, including actual physical touching, grabbing, kissing or attempted kissing, pinching, patting, and rubbing, all against their will" and accused Bruner of attempting to cover up the allegations.

[79] After serving as Florida's governor for the maximum two consecutive terms,[80] Bob Graham was elected to the United States Senate in November 1986.

He soon announced that he planned to resign as Florida's governor to assume his new role on January 3, several days before the end of his term.

[89][90] In April 1987, he wrote a letter criticizing a proposed 5% sales tax on insurance premiums and called for mass protests against it.

[93] In 1988, Martinez appointed Mixson to serve as the director of PRIDE, which ran prison industries in Florida.

[99] During the 1994 Florida gubernatorial election Mixson supported incumbent Democratic Governor Lawton Chiles against Republican nominee Jeb Bush.

[109] Mixson was in favor of allowing abortions in the cases of rape, incest, deformity, and if the health of the mother was threatened.

The legislation also gave governing bodies the ability to designate another official with the power to declare a state of emergency.

[116] Mixson cosponsored legislation created by Charles Papy that would prohibit gender discrimination in employment, banking, and education.

[118] Despite personally being against the Equal Rights Amendment he lobbied for its passage while serving as Governor Graham's chief lobbyist.

[119] In 1967, the state House of Representatives voted 61 to 53, with Mixson against, against legislation that would require a majority of the members of a jury to support the use of capital punishment.

[124] In 1979, Mixson supported Graham's decision to sign the death warrant permitting the execution of John Spenkelink, the first execution carried out after capitol punishment was reinstated, and stated that he and Graham were "strong supporters" of the death penalty when they were members of the state House.

[129] In 1973, Mixson and Lewis Earle co-wrote right-to-work legislation, which would prohibit the denial of work due to membership or non-membership of a union.

[132] In 1977, Mixson was one of twelve members of the state House of Representatives that was given a 0% rating by the Florida Education Association-United.

[133] During the 1979 oil crisis Mixson opposed the energy saving policy of banning gasoline sales on weekends proposed by President Jimmy Carter as it would cost Florida's economy $100 million and 29,000 jobs.

[136] During the 1978 gubernatorial campaign he stated that legalized casino gambling would reduce tourism to Florida as "families come here to see our beaches, and our natural wonders, but if we create a Las Vegas-type atmosphere, we'll lose them.