Breckinridge was born at "Cabell's Dale", near Lexington, Kentucky, to Joseph Cabell Breckinridge and Mary Clay Smith. He graduated from Centre College in Danville, Kentucky, in 1839, later attended the College of New Jersey (now Princeton University), and then studied law at Transylvania University in Lexington. He was admitted to the bar in 1840 and moved to Burlington, Iowa, but soon returned and began law practice in Lexington. He was married to Mary Cyrene Burch on December 12, 1843, in Georgetown, Kentucky. Breckinridge was a major of the 3rd Kentucky Volunteers during the Mexican-American War in 1847 and 1848.

Breckinridge was a member of the Kentucky House of Representatives, in 1849, as a Democrat, and was then elected to the Thirty-second and Thirty-third Congresses (March 4, 1851 – March 4, 1855). He did not run for reelection, and instead was nominated as Minister to Spain by President Franklin Pierce, but declined. He was elected Vice President of the United States in 1856, on the Democratic ticket with James Buchanan as President. He was the youngest Vice President in U.S. history, elected at the age 35, the minimum age required under the U.S. Constitution.

Breckinridge was an unsuccessful candidate for President in 1860, nominated by the Southern faction of the split Democratic Party and supported by the incumbent Democratic President, Buchanan. Far from expectant of victory, Breckinridge understood the long odds his success would necessitate. In a letter to Varina Davis he bemoaned "I trust I have the courage to lead a forlorn hope". In a four-way contest, he came in third in the popular vote, with 18.1%, but second in the Electoral College, winning the states of the Deep South, plus Delaware and Maryland. Breckinridge won the South with his pro-slavery platform, but was unable to win solid majorities in the border states, where Stephen Douglas, the Northern Democratic candidate, or the Constitutional Union Party was able to prevail in some cases. His native Kentucky went for John Bell, the Constitutional Union candidate. In most of the North, Breckinridge received almost no support, but as the candidate of the Buchanan faction he outpolled Douglas in Pennsylvania and won Delaware, and received some support comparable to Douglas in Connecticut. Republican Abraham Lincoln ultimately won the election with Breckinridge in second place. The race put Breckinridge at odds with his uncle, Robert Jefferson Breckinridge, who had supported Lincoln.

He was elected to the U.S. Senate in 1860 from Kentucky and served from March 4, 1861, until expelled by resolution of December 4, 1861, for support of the South. Fearing arrest, he fled to the Confederacy. Unlike other Confederate leaders, such as Robert E. Lee, who claimed obeisance to the will of their states, Breckinridge broke with his state after the Kentucky legislature voted to stay in the Union.

Breckinridge entered the Confederate States Army during the American Civil War as a brigadier general and soon became a major general, originally commanding the 1st Kentucky Brigade (nicknamed the Orphan Brigade because its men felt orphaned by a state government that did not support the Confederacy). He fought in many battles in the Western Theater, beginning with the Battle of Shiloh, in which he was wounded. He served as an independent commander in the lower Mississippi Valley, securing Confederate control of the area by taking Port Hudson.

Breckinridge developed an intense personal dislike of General Braxton Bragg, the commander of the Army of Tennessee. He considered him incompetent, a point of view shared by many other Confederate officers. Furthermore, Breckinridge felt that Bragg was unfair in his treatment of Kentucky troops in Confederate service, such as the Orphan Brigade. Throughout the war, Breckinridge felt a strong personal need to see to the welfare of his fellow Kentuckians. For his part, Bragg despised Breckinridge and tried to undermine his career with accusations that he was a drunkard. At the Battle of Stones River in Murfreesboro, Tennessee, Bragg ordered Breckinridge's division to launch a near-suicidal attack on the Union lines on January 2, 1863. Breckinridge survived the attack, but his division suffered heavy casualties. Breckinridge was devastated by the disaster; he lost nearly one third of his Kentucky troops, primarily the Orphan Brigade. As he rode among the survivors, he cried out repeatedly, "My poor Orphans! My poor Orphans."

Breckinridge continued to fight with Bragg's army, figuring prominently in the Confederate assaults on the second day, September 20, 1863, of the Battle of Chickamauga, and in the unsuccessful defense of Missionary Ridge in Chattanooga, November 25, 1863.

In early 1864, Breckinridge was brought to the Eastern Theater and put in charge of Confederate forces in the Shenandoah Valley. He defeated a superior Union force at the Battle of New Market, which included the famous charge of cadets from the Virginia Military Institute. Shortly thereafter, Breckinridge reinforced Robert E. Lee's Army of Northern Virginia and played an important role in the Battle of Cold Harbor, where his troops repulsed a powerful Union attack.

In the summer, Breckinridge participated in Lt. Gen. Jubal Early's Raid on Washington, moving north through the Shenandoah Valley and crossing into Maryland. He fought at the Battle of Monocacy in early July and was with Early when the Confederate force probed the defenses of Washington, D.C.. Since Lincoln was watching the fight from the ramparts of Fort Stevens, this was only time in American history when two former opponents in a presidential election faced one another across battle lines.

Following his service with Early's command, Breckinridge took command of Confederate forces in southwestern Virginia in September, where Confederate forces were in great disarray. He reorganized the department and led a raid into northeastern Tennessee. Following a victory outside of Saltville, Breckinridge discovered that some Confederate troops had killed black Union soldiers the morning after the battle, an incident that shocked and angered him. He attempted to have the commander responsible, Felix Huston Robertson, arrested and put on trial, but was unable to achieve this before the Confederacy disintegrated.

In early 1865, Breckinridge was made Confederate States Secretary of War, a post he would hold until the end of the war. Breckinridge saw that further resistance on the part of the Confederacy was useless and worked to lay the groundwork for an honorable surrender, even while President Jefferson Davis fiercely desired to continue the fight.

During the chaos of the fall of Richmond in early April 1865, Breckinridge saw to it that the Confederate archives, both government and military, were not destroyed but rather captured intact by the Union forces. By so doing, he ensured that a full account of the Confederate war effort would be preserved for history. Breckinridge went with Davis during the flight from Virginia as the Confederacy collapsed, while also assisting General Joseph E. Johnston in his surrender negotiations with William T. Sherman. Breckinridge continued to try to persuade Davis that further resistance would only lead to greater loss of life, but he also felt honor bound to protect the President from harm. Eventually, the two became separated in the confusion of the journey.

Breckinridge feared that he would be put on trial for treason by the United States government and resolved to flee the country. He and a small band sailed from Florida in a tiny boat to reach safety in Cuba. He continued to the United Kingdom, Canada, and the United Kingdom again. He returned to Lexington, Kentucky, in March 1869 after being granted amnesty, and resumed the practice of law. While turning down suggestions that he become active in politics again, he spoke out strongly against the Ku Klux Klan. He became vice president of the Elizabethtown, Lexington, and Big Sandy Railroad Company. He died in Lexington of complications from cirrhosis^[1] and was interred in Lexington Cemetery.

Breckinridge had ample reason to fear charges of treason. In 1863, premature rumors of his death prompted the New York Times to print what is perhaps the most vituperative obituary ever written about a nationally elected American official