Evidence of American Indian settlement in the area dates back 12,000 years. Following a series of failed uprisings with British support, however, the last Shawnee were forced to vacate the area before the end of the 18th century.
The first European descendant to settle in Owensboro was frontiersman William Smeathers or Smothers in 1797, for whom the riverfront park is named. The settlement was originally known as «Yellow Banks» from the color of the land beside the Ohio River. The Lewis and Clark Expedition wintered at what is today’s Owensboro prior to departing on their famous travels. In 1817, Yellow Banks was formally established under the name Owensborough, named after Col. Abraham Owen. In 1893, the spelling of the name was shortened to its current Owensboro
In August 1864, Owensboro was subject to a raid by a band of Confederate guerrillas from Tennessee led by Captain Jack Bennett, an officer in Stovepipe Johnson’s Partisan Rangers. Bennett’s men rode into Owensboro, tried and failed to rob a local bank, took 13 Union soldiers of the 108th Colored Infantry prisoner, executed them, burned the bodies on a supply boat, and escaped back to Tennessee, having covered a total of 300 miles (480 km) on horseback in six days. Another major battle occurred 8 miles (13 km) south of Owensboro and is today signified by a monument marking the battle located beside US Highway 431.
Several distillers, mainly of bourbon whiskey, have been in and around the city of Owensboro. The major distillery still in operation is the Glenmore Distillery Company, now owned by the Sazerac Company.
On August 14, 1936, downtown Owensboro was the site of the last public hanging in the United States. A 26 year old African American man, Rainey Bethea, was convicted and sentenced for the rape and murder of 70-year-old Lischa Edwards in a very short time (only 37 days lapsed between the crime and the execution). A carnival atmosphere was in place with vendors selling hotdogs, attended by a large crowd including children and many reporters.The execution was presided over by a woman sheriff, Florence Shoemaker Thompson, who gained national media attention for her role in the process, although she declined to spring the trap, which was instead released by a mob. Before Bethea was dead, the crowd had already begun to tear at his clothes and even his body for souvenirs. The Kentucky General Assembly quickly abolished public executions after the embarrassment this caused
The end of the Second World War brought civil engineering projects which helped turn Owensboro from a sleepy industrial town into a modern, expanding community by the turn of the 1960s. Many of the projects were set in motion by Johnson, Depp & Quisenberry, a firm of consulting engineers then engaged in a runway redesign at the County Airport; the «Depp» in question was a member of an old and prominent Kentucky family which includes the town’s most famous son, actor Johnny Depp.
As of 1903, Owensboro was home to several stemmeries.Pinkerton Tobacco produced Red Man chewing tobacco in Owensboro. Swedish Match continues to make Red Man in a plant outside city limits.