Indigenous peoples lived along the Mississippi River and related waterways for thousands of years before European contact. French Jesuit priests in the Illinois Country encountered the Kaskaskia and Cahokia, bands of the Illiniwek confederacy.
The first European settlement in this area was St. Philippe, founded in 1723 by Philippe François Renault, a French courtier, on his concession about three miles north of Fort de Chartres along the Mississippi River. This early agricultural community quickly produced a surplus, and grains were sold to the lower Louisiana colony for years. They were integral to that community's survival, as its climate did not allow cultivation of such staple grains.
Beginning on the Mississippi River where the base line, which is about three-fourths of a mile below Judge Briggs's present residence, strikes the said river; thence with the base line until it strikes the first township line therefrom; thence southeast to the southeast corner of township two south, range nine west; thence south to the southeast corner of township four north, range nine west; thence southwestwardly to the Mississippi, so as to include Alexander McNabb's farm, and thence up the Mississippi to the beginning shall constitute a separate county, to be called MONROE.
It was named in honor of James Monroe, who had just served as United States Secretary of War and who was elected President later that same year. Its first county seat was Harrisonville, named for William Henry Harrison, former governor of the Northwest Territory and future President. Harrison invested in several tracts of land in the American Bottoms above Harrisonville, mostly in the present precinct of Moredock, ownership of which he retained until his death.
Waterloo was designated as the mantle of county seat in 1825. The sites of the colonial towns of St. Philippe and Harrisonville were submerged by the Mississippi River, in flooding caused by deforestation of river banks during the steamboat years. Crews cut so many trees that banks destabilized and collapsed in the current, making the river wider and more shallow from St. Louis to the confluence with the Ohio River. This change caused more severe flooding, as well as lateral channel changes, such as the one that cut off the village of Kaskaskia from the Illinois mainland.
An unincorporated community of Harrisonville was re-established east of the original site. The bounds of Monroe County in 1816 did not include Precincts 1 and 6 (village of Hecker and Prairie du Long), Precinct 1 and most of 6 was added in 1825 from St. Clair County. The strip of Precinct 6 from the survey township line east to the Kaskaskia was added, once again from St. Clair, two years later in 1827. Some minor adjustments and clarifications of the boundaries have taken place, but the borders have remained essentially static since 1827.