[2] The county was organized February 14, 1845, and named for General John F. Mercer of the Revolutionary War.

[3] It is named in honor of General Hugh Mercer, who fought and died in the American Revolutionary War.

The first permanent settlements in what is now Mercer County were in 1837, when a few families from other parts of Missouri moved to the area.

Prior to 1837, the land was used by Native American tribes, primarily the Sac/Fox and Potawatomi, as prime hunting grounds.

The town of Princeton, named for the battle where General Mercer was killed, was established as the county seat in 1847.

The boundary was 9.5 miles farther north than present day prior to an 1851 decision by the U.S. Supreme Court.

Most county residents had roots in northern U.S. states "back east" like Pennsylvania, Ohio, and Indiana, and did not have the strong slave-holding tradition of other northern Missouri counties like Macon, Audrain, and Monroe (commonly referred to as Little Dixie), whose population largely emigrated from Southern states.

In the 2020 presidential election, Mercer County had the highest Republican turnout in the state of Missouri with greater than 86% of the population voting for Donald Trump.