The county was organized January 6, 1831[3] and named for James Monroe, the fifth President of the United States.

[4] Monroe County was one of several along the Missouri River settled by migrants from the Upper South, especially Kentucky and Tennessee.

They brought slaves and slaveholding traditions with them and quickly started cultivating crops similar to those in Middle Tennessee and Kentucky: hemp and tobacco.

The Democratic Party used to dominate politics at the local, state and federal levels in Monroe County.

In 2016, for the first time in history, Ron Staggs, a Republican, was elected to a county office when he defeated a Democratic opponent for western commissioner.

In 2022, Curt Wheeler beat a Democrat and an Independent, to become the county's first Republican presiding commissioner.

In the 2008 general election, notwithstanding the secretary of state's race, for the first time in history, Monroe Countians gave a plurality to every Republican candidate for federal and state offices, on the ballot, that had a Democratic opponent.

Four years later, in the 2012 election, Republican candidates won six of eight state-wide state and federal races, and one was lost by five votes out of more than 4,000 cast.

In November 2016, 2018, 2020, 2022 every Republican for federal and state office, on the county ballot, defeated their Democratic opponent.

The county was one of only two jurisdictions in Missouri to be carried by Democrat George McGovern in the 1972 presidential election against incumbent Republican President Richard Nixon, the other being the city of St. Louis.

Monroe County was first carried by a Republican in 1976 by John Danforth in the U.S. Senate race.