At the war’s conclusion, Breckinridge was elected to Kentucky's lower house (1849-1851) as a states’ rights Democrat before winning a seat in the U.S. House of Representatives (1851-1855).  He played a key role in incorporating the repeal of the Missouri Compromise ban on slavery into Stephen Douglas’s Kansas-Nebraska Act and in securing House approval for the final bill (1854).  Breckinridge himself sponsored no major legislation, but was a popular political figure.  In 1856, delegates to the Democratic National Convention selected him as James Buchanan’s vice-presidential running mate.  Inaugurated when only 36 years old, he has the distinction of being the youngest vice president in American history.  

When the Democratic Party split into sectional factions in 1860, Breckinridge was nominated for president by the Southern wing.  Concerned that a divided party would allow the Republicans to triumph, he offered to decline the nomination if Douglas would reject his nomination by the Northern wing.  Douglas declined the proposition, and both men remained in the race.  Although Breckinridge was a slaveowner who supported the constitutional protection of slavery and the right of secession, he was not one of the radicals.  In the November 1860 election, Breckinridge captured all the states in the Deep South, but as he had feared, Republican Abraham Lincoln won the presidency with an Electoral College majority. 

During the interval between Lincoln's election and his inauguration in March 1861, Breckinridge worked for a compromise between the North and South.  In early 1861, the Kentucky legislature again elected him to the U.S. Senate, and he took his seat in March.  When the Kentucky state government declared in late May 1861 that it was officially neutral in the Civil War, Breckinridge supported its right to do so, even though he personally opposed the policy.  A Confederate invasion of western Kentucky in early September prodded an angered Kentucky legislature to throw its support to the Union cause.  A few days later, the body declared that Breckinridge and Powell no longer represented the state of Kentucky.

On October 8, Breckinridge responded in a heated speech against the Union's allegedly harsh treatment of Missouri and Maryland, two other important Border States (slave states loyal to the Union).  He warned that Kentuckians would henceforth have "to deal with a power which respects neither the Constitution nor laws, and which, if successful, will reduce you to the condition of prostrate and bleeding Maryland."  In early November, a federal court in Kentucky returned indictments for treason against 32 prominent Kentuckians, including Breckinridge.  Within a few weeks, he left the halls of Congress, was commissioned a brigadier general in the Confederate Army, and took command of the First Kentucky Brigade.  On December 4, 1861, the U.S. Senate expelled John C. Breckinridge from its membership.

Breckinridge accumulated a notable military record during the Civil War, fighting at Bowling Green, Shiloh, Baton Rouge, Stones River, Vicksburg, Chickamauga, and Missionary Ridge.  He rose to the rank of major general, and then served as the Confederacy’s last secretary of war during the closing months of the war.  He opposed efforts to prolong the war with guerrilla fighting after Robert E. Lee’s surrender at Appomattox on April 9, 1865.  Following the war Breckinridge fled to Cuba, then to England, and finally to Canada.  President Andrew Johnson pardoned him on Christmas Day 1868, allowing him to return to Kentucky a few months later.  Although he forswore electoral politics, Breckinridge urged sectional reconciliation and criticized the Ku Klux Klan.  He was employed as a railroad executive until his death in 1874.