[6] According to Goodspeed's History of White County, the Calfkiller River is likely named after a Cherokee chief who lived in the valley when the first European-American settlers arrived in the area around 1800, following the American Revolutionary War.

In the years before the Civil War, an iron works and a cotton mill operated along the banks of the river in the vicinity of the current TN-111 bridge.

On August 9, 1863, Union forces under Charles Minty attacked a Confederate scouting detachment under George Dibrell near Wildcat Creek, eventually scattering the Rebels after intense fighting.

Another skirmish occurred on November 30 of that year, when a band of Confederate guerrillas unsuccessfully ambushed a detachment of the U.S. First Tennessee Cavalry at Yankeetown.

On February 22, 1864, a band of Confederates under John Hughes attacked a detachment of the Fifth Tennessee Cavalry along the river, in what became known as the "Battle of Dug Hill."

[10] Confederate guerrilla leader Champ Ferguson, who lived in the Calfkiller Valley, is buried in France Cemetery, along the banks of the river near the Putnam-White county line.