Breckinridge was born at "Cabell's Dale", near Lexington, Kentucky. He graduated from Centre College in Danville, Kentucky in 1839 and later attended the College of New Jersey (now Princeton University). He was admitted to the bar in 1840 and moved to Burlington, Iowa, but soon returned and began practice in Lexington. Breckinridge was a major of the Third Kentucky Volunteers during the Mexican-American War in 1847 and 1848. He was a member of the state House of Representatives in 1849. He was elected as a Democrat to the Thirty-second and Thirty-third Congresses (March 4, 1851-March 3, 1855). Breckinridge did not run for reelection, and instead was nominated as Minister to Spain by President Franklin Pierce, but declined. He was elected Vice President in 1856 on the Democratic ticket with James Buchanan as President.
Breckinridge was an unsuccessful candidate for President in 1860. He lost to Abraham Lincoln. He was elected to the United States Senate and served from March 4, 1861 until expelled by resolution of December 4, 1861, for support of the rebellion;. He entered the Confederate Army during the American Civil War as a Brigadier General and soon became a Major General, then served as Secretary of War in the Cabinet of the Confederate States of America from January until April 1865.
Breckinridge resided in Europe until 1868, when he returned to Lexington and resumed the practice of law. He became vice president of the Elizabethtown, Lexington Big Sandy Railroad Company, then died in Lexington. He was interred in Lexington Cemetery.