When Combs won the governorship in 1959, he appointed Breathitt as personnel commissioner, where he wrote legislation establishing the first merit system for state employees.

His major accomplishment as governor was the passage of the Kentucky Civil Rights Act, the first desegregation law passed by a southern state.

He engaged in numerous community service activities and served on political commissions aimed at eliminating poverty.

[5] Seeing Breathitt's interest in politics, professors Jack Reeves and Thomas D. Clark asked him to chair the campus campaign supporting a new state constitution.

[5] Bert T. Combs put Breathitt in charge of his campaign against Wilson Wyatt in the Democratic gubernatorial primary in 1958.

[7] After successfully guiding the legislation through the General Assembly, Breathitt resigned as personnel commissioner to accept an appointment to the Kentucky Public Service Commission.

[7] He was also served as chair of a failed state constitutional convention in 1960 and was a member of the Governor's Commission on Mental Health.

[10] The anti-Chandler faction became concerned that, if they did not name a candidate, Chandler's early announcement would give him an advantage in the 1963 election.

[10] Leaders of the faction were solidly behind state Highway Commissioner Henry Ward, but Governor Combs was leaning toward Breathitt.

[14] He further charged that Chandler's son-in-law was collecting campaign donations from individuals who desired favors from state government.

[14] The younger Breathitt, thirty-eight years old when the campaign began, adapted well to the relatively new medium of television, while the aging Chandler did not.

[15] Still stinging from his primary defeat, Happy Chandler endorsed Nunn, which hurt Breathitt with some members of his own party.

[18] Further, the unexpected death of Richard P. Moloney, a key legislative leader, was a blow to Breathitt's ability to push his agenda through the General Assembly.

[18] The major accomplishment of the 1964 session was the approval of a $176 million bond issue to increased funding for roads, public education, the state park system, and social services.

[18][19] Other minor accomplishments included passing a purchasing law, strengthening strip mining regulations, and improving benefits for teachers.

[18] A rally in favor of the bill was held in March and was attended by Dr. Martin Luther King Jr., Reverend Ralph Abernathy, and baseball player Jackie Robinson.

[20] As a member of the Southern Governors' Association (SGA) in October 1964, Breathitt was one of three governors to oppose George Wallace's proposed constitutional amendment to give states and state courts sole jurisdiction over their public schools, preventing a federal law to integrate them.

[18][23] County leaders opposed the document because of perceived threats to the independence of local governments and an apparent consolidation of power in Frankfort.

[5][24] The pro-administration majority in the legislature was expanded in the 1965 elections, and Waterfield, Breathitt's sometimes hostile lieutenant governor, was stripped of much of his authority.

[23][24] Former governor Lawrence Wetherby was selected president pro tempore of the senate, providing effective leadership in that house of the General Assembly.

[23] Wetherby introduced a budget which was 27 percent larger than the previous one and contained appropriations for most of the state's political districts.

[24] Wetherby's leadership was so effective that the budget passed both houses of the Assembly, virtually unchanged, by votes of 99–0 and 31–5 only ten days later.

[2][5] In the 1966 legislature, he won approval for several conservation measures, including the creation of an authority to regulate water, soil, and forest resources.

[26] In July 1968, he was named director of the Ford Foundation's Institute for Rural America, suggesting legislative remedies for poverty including the establishment of state area development districts.

[26] Breathitt also served as president of the American Child Centers to promote private preschool education and was appointed as the federal representative on the Southern Interstate Nuclear Board in September 1968.

[5] He undertook several volunteer community service activities, including serving as director of Home Loan Bank in Cincinnati and chairman of the Kentucky Heart Fund.

[5] While giving a speech at Lexington Community College on October 10, 2003, Breathitt collapsed due to ventricular fibrillation.