Except for a few miles near its head, its mouth, and near the middle of its length, it has been entirely channelized, as have its major tributaries, for agriculture purposes.

The Loosahatchie rises in the westernmost part of Hardeman County, Tennessee, and flows largely east to west throughout its length.

It enters Fayette County, Tennessee, flowing through Somerville, and is crossed west of there by Interstate 40 in the only unchannelized portion of its midcourse.

It meets the Mississippi north of the mouth of the Wolf River near Mud Island.

Slightly downstream from its mouth in the main Mississippi channel is the Loosahatchie Bar, which is named for it.