During his term as lieutenant governor, Breathitt was one of several proposed candidates to succeed John Rowan in the United States Senate.

Initially, Breathitt enjoyed popularity for his public condemnation of John C. Calhoun's doctrine of nullification, but he struggled in state politics because the Whigs controlled the legislature.

Two younger brothers later also became active in politics: George Breathitt served as a private secretary to President Andrew Jackson.

[3] Their sister Jane Breathitt married Dr. John Sappington from Nashville, Tennessee, and the couple moved to central Missouri territory in 1817.

But he became nationally known for his development of a patent medicine: quinine pills to treat malaria and other fevers, which were widespread in the Missouri and Mississippi valleys.

On December 31, 1829, he was elected president of the Kentucky Educational Society, whose stated mission was to "promote improvement and diffusion of popular education by the circulation of information, by enlisting the pulpit and the press, by procuring the delivery of popular addresses on the subject on the 4th day of July, and in different neighborhoods, and by other means that may be found practicable.

[8] In 1831, Breathitt was one of several candidates put before the General Assembly to succeed John Rowan in the United States Senate.

[2] They faced a Whig (formerly National Republican) ticket of Richard Aylett Buckner and James Turner Morehead.

[10] Buckner was hurt by his highly religious ideals, including opposition to handling mail on Sunday, and failed to garner the support of some of his own party's newspapers.

[10] Most Kentuckians were more concerned about the upcoming presidential election, hoping Whig and native son Henry Clay would defeat Democrat Andrew Jackson.

[10] Early in his term, Breathitt won favor from both Whigs and Democrats by opposing South Carolina's actions during the Nullification Crisis.

Following Breathitt's lead, the state legislature passed resolutions condemning the doctrine of nullification on February 2, 1833.

This action was particularly significant because John C. Calhoun's justification for nullification was largely based on the 1799 Kentucky Resolutions.

He ardently supported Jacksonian principles, and wielded his veto against bills critical of President Jackson's land policy.

[12] When the Kentucky Legislative Temperance Society was formed at a meeting in the state house on January 13, 1834, Breathitt was chosen as its president and Lieutenant Governor Morehead served as one of five vice-presidents.

[2] On March 5, 1872, the Kentucky General Assembly resolved to erect a monument over Breathitt's grave in Russellville.