To help attract people to purchase land and populate the region, Henderson & Co. hired pioneer, explorer, woodsman, and frontiersman Daniel Boone to lead settlers through Cumberland Gap and direct woodsmen to cut the Wilderness Road through the Kentucky forest.

However, the Continental Congress declined to act on Transylvania Co.'s petition without the consent of Virginia and North Carolina, which laid claim to the disputed lands.

The location they selected for the town was the site of an existing settlement that sat high above the Ohio River called Red Banks.

[6] In August 1799, serial killers Micajah and Wiley Harpe came to the house of Moses Stegall, near what is now Dixon in Webster County, and murdered his wife, child, and a visitor.

Moses Stegall later tracked down the brothers, and killed Micajah Harpe, cutting off his head and hanging it in a tree as a warning to other outlaws.

During the 19th century, a cultivar of dark tobacco raised in Henderson County became very popular in Great Britain and continental Europe.

[8] A peninsula across the Ohio from Henderson, which now forms Union Township, Vanderburgh County, Indiana, was the subject of Handly's Lessee v. Anthony, a U.S. Supreme Court case in 1820.

A workplace shooting occurred at an Atlantis Plastics factory in Henderson, Kentucky, United States on June 25, 2008.

The gunman, 25-year-old Wesley Neal Higdon, shot and killed five people and critically injured a sixth, before taking his own life.

[10] The mass murder is the worst in the history of Henderson County, surpassing the triple homicides that took place in 1799 and 1955.