Blackburn was the first doctor elected governor of the Commonwealth and was the only one until the election of Ernie Fletcher in 2003. His major issue as governor was prison reform. He was called the "father of prison reforms in Kentucky" for his efforts in improving conditions in the state's penal system.
One incident stands in dark contrast to the rest of Blackburn's life. During the Civil War, he deliberately shipped trunks of clothing and linens contaminated with yellow fever to Northern cities in order to begin a pandemic of the disease and cripple the Union economy. Though it was later discovered that mosquitos are responsible for the spread of yellow fever, the plot is believed to be one of the earliest attempts at biological warfare in the United States.
It was, however, the profession of another relative his uncle Churchill Blackburn, a noted physician in Paris, Kentucky that interested him. Shortly after his sixteenth birthday, young Luke began a two-year apprenticeship under his uncle, helping him minister to residents of Kentucky's Bluegrass region during an outbreak of cholera in 1833. Following his apprenticeship, Blackburn entered medical school at Transylvania University, earning an M.D. in March 1835. He then began practicing in Lexington, Kentucky.
On November 24, 1835, Blackburn married Ella Gist Boswell, the daughter of Lexington physician Joseph and Judith Bell Boswell. Dr. Boswell had died in the cholera outbreak two years earlier. Blackburn and Boswell had one son, Cary Bell.
It was during a cholera outbreak in nearby Versailles, Kentucky that Blackburn's reputation as a physician and philanthropist began to escalate. He often offered his services for free to ailing victims of the disease.
After a failed business venture involving the manufacture of rope and bagging, Blackburn was elected as a Whig to the Kentucky House of Representatives in 1843. Despite his family history, politics apparently did not agree with him; he refused to seek a second term, instead opening a medical practice with his brother in Frankfort, Kentucky.
His concern for boatmen working along the Mississippi River lead him to set up a hospital for them using his own money. Mississippi Congressman Albert G. Brown used Blackburn's generosity to chide Congress for not providing adequate medical facilities for the boatmen. Brown's pleas were heeded, with Congress appropriating $60,000 for the construction of six facilities along the Mississippi. One of these facilities was constructed in Natchez, and Blackburn was named chief physician.
His successful quarantines in Natchez led Blackburn to lobby the Louisiana State Legislature to establish a quarantine station along the river below New Orleans to prevent the spread of yellow fever upstream. The measure was approved in 1855 over the protests of merchants who claimed it would hurt commerce, though the merchants' considerable influence rendered it ineffective in subsequent years.
In November 1856, Blackburn's wife Ella, who suffered from dropsy and a nervous condition, died of "a fever." Grief-stricken, Blackburn was encouraged by family members to take the European trip he'd often talked about taking. In 1857, Blackburn made the trip, touring the hospitals England, Scotland, Germany, and France. While in Paris he encountered fellow Kentuckian Julia M. Churchill. Upon returning to Kentucky in November 1857, Blackburn married Churchill. The couple took up residence in New Orleans.
On two separate occasions in 1864, Blackburn sailed for the Caribbean island of Bermuda, where yellow fever was running amok. On both occasions, he arranged for trunks filled with linens and clothing used by his patients to be imported to Northern cities, believing yellow fever could be introduced into the area in this way. It was later alleged that some of the contaminated clothing was intended for President Lincoln himself.
In April 1865, Blackburn's plot was uncovered. The U.S. Bureau of Military Justice charged him with conspiracy to commit murder, but he remained in Canada to avoid prosecution. He was, however, tried in Toronto for violating Canada's neutrality in the war, but was acquitted.
Reform of Kentucky's penal system was the hallmark of Blackburn's term as governor. He appointed a commission to oversee drastic improvements at the eighty-year-old penitentiary in Frankfort, ominously dubbed "Kentucky's Black Hole of Calcutta by some. He secured funding for the Kentucky State Penitentiary at Eddyville, Kentucky, though it never became what Blackburn envisioned a facility that would "teach and train the prisoner in such a manner that on his discharge, he may be able to resist temptation and inclined to lead an upright and worthy life." He also hired out convicts to work on public projects.
Blackburn financed his reform measures by increasing the state's property tax. The use of tax dollars to improve the lot of prisoners was an unpopular action, and had prevented previous prison reform advocates from accomplishing the needed improvements. Blackburn forced the General Assembly's hand by liberally invoking his power of executive pardon, releasing the aged and infirm to alleviate overcrowding. This action earned him the nickname "Lenient Luke."
Other accomplishments during Blackburn's administration included revamping the state's district courts, creating a state superior court, and reorganizing the Agricultural and Mechanical College later, the University of Kentucky.