This area was historically occupied by the Osage and other Native American peoples, some of whom migrated from east of the Ohio River Valley.
The early European-American settlement of Callaway County was largely by migrants from the Upper South states of Virginia, Kentucky, and Tennessee, with an influx of German immigrants starting in the 1830s, as was the case with other counties along the Missouri River. Some of them brought African-American slaves and slaveholding traditions with them, and quickly started cultivating hemp and tobacco, the same crops as were grown in Middle Tennessee and Kentucky. Given their culture and traditions, this area became known as Little Dixie.
The Battle of Moore's Mill was the only significant Civil War battle that took place in Callaway County. One historian said it was known as 'Kingdom of Callaway'. A truce with US/Union forces during the war effectively allowed Confederate advocates to continue to operate under surveillance, in proximity to the Missouri government offices in Jefferson City. There may have been more than twice as many Confederate as US/Union troops in Callaway.
According to "A Short History of Callaway County" by Ovid Bell, the publisher of the (county seat) Fulton Daily Sun Gazette, "Fulton was occupied during the greater part of the war by Union soldiers and militia, and Southern (i.e. Confederate) sympathizers were in constant fear of imprisonment and death." US forces loyal to the Union were raised by Captains William T Snell, Henry Thomas, and JJP Johnson. They were reinforced by troops under General John B Henderson from the town of Louisiana in Pike County, Missouri.
Callaway has remained largely agricultural, economically, with its rich farmlands, yet borders Missouri's capital city and Lincoln University (Missouri) in Cole County, to the south, and the main University of Missouri campus in Columbia, 40 miles or less from the most populous areas of the county. Callaway County has for years hosted William Woods University and Westminster College in the county seat, Fulton, while Osage county, to the south, hosts the State Technical College of Missouri in Linn.