The county was organized in 1820. It was named for Capt. James Callaway, a grandson of Daniel Boone. Callaway was killed in Indian fighting in 1815.
Callaway County is also referred to as "The Kingdom of Callaway", after an incident in which residents confronted Union troops during the American Civil War.
Summit Lake Winery was founded in Holts Summit, linking the county to the Missouri Rhineland along the river. Vineyards and wineries were first established in the area by German immigrants in the 19th century. Since the 1960s, there has been a revival of winemaking throughout the state.
As of the census of 2000, there were 40,766 people, 14,416 households, and 10,336 families residing in the county. The population density was 49 people per square mile (19/km²). There were 16,167 housing units at an average density of 19 per square mile (7/km²). The racial makeup of the county was 91.79% White, 5.66% Black or African American, 0.52% Native American, 0.52% Asian, 0.01% Pacific Islander, 0.30% from other races, and 1.21% from two or more races. 0.92% of the population were Hispanic or Latino of any race. 29.9% were of German, 22.0% American, 9.1% Irish and 9.1% English ancestry according to Census 2000.
There were 14,416 households out of which 35.80% had children under the age of 18 living with them, 57.10% were married couples living together, 10.40% had a female householder with no husband present, and 28.30% were non-families. 23.00% of all households were made up of individuals and 8.80% had someone living alone who was 65 years of age or older. The average household size was 2.56 and the average family size was 3.00.
In the county the population was spread out with 25.40% under the age of 18, 11.10% from 18 to 24, 31.00% from 25 to 44, 21.50% from 45 to 64, and 11.00% who were 65 years of age or older. The median age was 35 years. For every 100 females there were 107.60 males. For every 100 females age 18 and over, there were 108.90 males.
The median income for a household in the county was $39,110, and the median income for a family was $44,474. Males had a median income of $29,574 versus $22,317 for females. The per capita income for the county was $17,005. About 6.00% of families and 8.50% of the population were below the poverty line, including 10.30% of those under age 18 and 8.30% of those age 65 or over.