Cape La Croix, a rock island in the Mississippi River, has a cross erected by Jesuit missionary Father De Montigny, who traveled with early French explorers in 1699.

Some French colonists established trading relationships with the Osage; the traders were based in St. Louis, founded in the late 18th century.

They laid out the King's Highway (El Camino Real) in 1789, a north–south route crossing the county and extending through St. Louis, Missouri.

France briefly took back the territory, then sold it to the United States in 1803 as part of the Louisiana Purchase.

Delaware (Lenape) and Shawnee people migrated into the area in the 1820s from territories east of the Mississippi, pushed by European-American encroachment on their lands.

[3] One of the earliest settlements was Commerce, Missouri, long known as Tywapitty, derived from an Osage language term.

Sikeston, the largest city in the county and the fourth settlement to be founded, was settled in 1800 and was laid out in 1860 by John Sikes on the Cairo & Fulton Railroad.

Afterward, it developed rapidly from the 1870s to the early 1900s; its dense forests were lumbered off and numerous railroads were constructed.

Towns founded during this period included Diehlstadt, Morley, Oran, Perkins, Blodgett, Crowder, Vanduser, Illmo, Fornfelt (Scott City), Chaffee, Ancell, and Kelso.

Between the Mississippi River and Little River District drainage ditches lies one of the oldest drainage systems in the United States, Crowley's Ridge, established in 1905, is a remnant of an old coastal floodplain and natural levee that crosses the country.

A Scott County all-white grand jury did not return any indictments for the crime after three hours of deliberation.

The most predominant denominations among residents in Scott County who adhere to a religion are Southern Baptists (40.54%), Roman Catholics (27.12%), and Methodists (9.28%).

In recent years, however, Republicans have made inroads, gaining control of several county offices in 2018 and 2020.

[22] A shift began to become evident in the 1980s, as Scott County voted Republican thrice in a row for the first time, one of those times even being against Southerner Jimmy Carter; however, all three elections were nationally decisive Republican wins, and Bill Clinton was able to recapture the county, albeit not by large margins, in both of his wins.

Like most rural areas throughout Southeast Missouri, voters in Scott County generally adhere to socially and culturally conservative principles.

The proposition strongly passed every single county in Missouri with 75.94 percent voting in favor as the minimum wage was increased to $6.50 an hour in the state.