White settlement along the river began in the early 1820s as pioneers ventured up the valley from Howard County, Missouri.

The Sac-Fox had ceded all hunting rights to northern Missouri in 1825, but Big Neck and his band of Iowa refused to acknowledge the transaction.

As had the Native Americans before them, early settlers found an area rich with game for hunting, ample fish in the river, and large stands of timber.

According to the Missouri Department of Conservation, "public use of Chariton River watershed streams is very low, largely because instream habitat has been so adversely affected by channelization and sedimentation".

Because of extensive channeling the Little Chariton River, formerly a tributary, now flows directly into the Missouri about 7 miles (11 km) from the main branch.