John Breckinridge was born in Lexington, Kentucky, to Mary Smith Breckinridge and John Cabell Breckinridge Sr. The family had a tradition of holding public office. Young Breckinridge's father was a state representative and his grandfather had been a U.S. senator. The senior John Breckinridge died in 1823 leaving his son to be raised by the boy's mother and grandmother. In 1839 the young man graduated from Centre College (Kentucky), then studied law at the College of New Jersey before completing his degree at Transylvania University (Kentucky) in 1841. He opened a law practice in Burlington, Iowa, but two years later returned to Kentucky, where he prospered in the profession.

During the Mexican War Breckinridge served as a major with the Kentucky volunteers. At the war's conclusion, he was elected to the state's lower house (1849-1851) as a states' rights Democrat, then won a seat in the U.S. House of Representatives (1851-1855). He played a key role in adding the repeal of the Missouri Compromise ban on slavery to Stephen Douglas's Kansas-Nebraska Act and in securing House approval for the final bill. 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 was the youngest vice president in American history. Buchanan did not include him in policy-making, so the vice president eagerly awaited returning to the U.S. Senate upon John Crittenden's retirement in 1861.

When the Democratic party split into sectional factions in 1860, Breckinridge was nominated for president by the Southern wing, who called themselves the National Democrats. 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, 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. He captured all the states in the Deep South, but Lincoln won the presidency with an electoral-college majority.

During the interval period, Breckinridge worked for a compromise and supported the attempt by Kentucky's government to remain neutral. When Kentucky formally sided with the Union in September 1861 and state officials tried to arrest him, he joined the Confederate army as a brigadier general. He accumulated a notable military record, fighting at Bowling Green, Shiloh, Baton Rouge, Stones River, Vicksburg, Chickamauga, and Missionary Ridge. He rose to the rank of major general, then served as the Confederacy's last secretary of war during what would be the closing months of the war. He opposed efforts to prolong the war with guerrilla fighting after Lee's surrender.