Early in his career, he became an emancipationist, and he entered academia in 1831 when he began teaching ancient languages at Centre College in Danville, Kentucky.

[2][5] In the early to mid-1820s, Breckinridge and several of his brothers became vocal proponents of antislavery, aligning themselves in the minority; the abolitionist James G. Birney wrote that the men "had disqualified themselves from political usefulness" as a result.

[6] Breckinridge was among the organizers of the Kentucky Colonization Society, whose goal was to emancipate slaves and then provide transport for them back to Africa.

[7] In 1849, he attended the Friends of Emancipation state convention, held in Frankfort, along with his brother Robert, Cassius Marcellus Clay, John C. Young, and Walter Newman Haldeman.

[11] He was active in his advocacy against slavery as well and spoke in Shelbyville, Lexington, Brunerstown, Jeffersontown, and Louisville throughout 1849, the last of which was a debate against the lawyer William Christian Bullitt.

He held the pastorate in Louisville until he resigned in ill health in 1858; he briefly preached at several churches in Woodford County in the following months.

[15] There, he oversaw the selection of a new site for what would become the Presbyterian Theological Seminary of the Northwest, at the time located in New Albany, Indiana; Indianapolis and Chicago were the candidate cities and the latter was ultimately selected due in part to a $100,000 (equivalent to $3.5 million in 2024) donation from Cyrus McCormick and allowance for the use of 45 acres of land from a separate group.

[2] In 1860, Breckinridge returned to academia when he accepted a position as president of Oakland College near Rodney, Mississippi, succeeding James Purviance.

[21] Centre remained open throughout the duration of the war but suffered nonetheless, as did the town; Confederate guerilla outlaws William Quantrill and Frank James led a stint of violence in Danville in January 1865 that included the destruction of the city bookstore and telegraph office, as well as the robbery of numerous citizens at gunpoint.