Settled primarily by migrants from the Upper South during the nineteenth century, this county was in the region bordering the Missouri River known as "Little Dixie".

In the antebellum years, it had many plantations operated with the forced labor of enslaved workers.

Saline County was occupied for thousands of years by succeeding cultures of Missouri Native Americans.

[3] After periods of conflict as settlers competed for resources and encroached on their territory, the local Native Americans, including the Osage nation, were forced by the U.S. government to move to reservations in Indian Territory, first in Kansas and then in Oklahoma.

Saline County was among several along the Missouri River that were settled primarily by migrants from the Upper South states of Kentucky, Tennessee and Virginia.

The settlers quickly started cultivating crops similar to those in Middle Tennessee and Kentucky: hemp and tobacco; they had brought enslaved people with them to central Missouri, or purchased them from slave traders.

By the time of the Civil War, one-third of the county population was African American; most of them were enslaved laborers on major plantations, particularly for labor-intensive tobacco cultivation.

By the early 20th century, Saline County had eighteen schools for black students.

The largely rural county reached its peak of population in 1930, and has slowly declined since then since mechanization of farming has meant that fewer workers are needed; from about 1910 to the 1970s, African Americans often moved to larger urban areas for work and better social conditions.