[2] The county was officially organized on December 11, 1818, and is named after General "Mad" Anthony Wayne, who served in the American Revolution.

[3] As of August 28, 2023, Wayne County is designated the UFO Capital of Missouri, along with the city of Piedmont.

The small strip that had been excluded was added to Wayne County by the Missouri State Constitution of 1820.

Between 1825 and 1831, Wayne County was actually larger than the states of Massachusetts, Connecticut, Rhode Island, and Delaware combined.

Despite its size, the Census of 1820 revealed that Wayne County had a total population of just 1,239 white inhabitants and 204 African American slaves.

They chose a small settlement called Cedar Cabin on the St. Francis River to be the county seat.

According to the 2000 Census, the most common first ancestries reported in Wayne County were 32.9% American, 15.0% German, 11.9% English, 11.7% Irish, 3.0% French (excluding Basque), 2.0% Dutch and 2.0% Italian.

The most predominant denominations among residents in Wayne County who adhere to a religion are Southern Baptists (62.76%), Methodists (10.08%), and Roman Catholics (7.07%).

The Republican Party dominates politics at the local level in Wayne County and controls all but one county-wide offices.

Smith won a special election on Tuesday, June 4, 2013, to finish out the remaining term of U.S. Representative Jo Ann Emerson (R-Cape Girardeau).

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.

In the 2008 presidential primary, voters in Wayne County from both political parties supported candidates who finished in second place in the state at large and nationally.

Senator Hillary Clinton (D-New York) received more votes, a total of 1,458, than any candidate from either party in Wayne County during the 2008 presidential primary.