The river drains a mostly rural area and forms part of the Missouri-Arkansas state line along the western side of the Missouri Bootheel.

It forms the Missouri-Arkansas border in the Bootheel and eventually exits the state at Missouri's lowest point in the "toe" at 241 feet (73 m) above sea level.

It joins the Mississippi River in Phillips County, Arkansas, about 7 miles (11 km) north of Helena.

Along its course in Missouri, the river flows through the Mark Twain National Forest and past Sam A. Baker State Park and the towns of Farmington, Greenville and Fisk.

[5] The Spanish authorities allowed the Indian settlement to trade and the area flourished with a population greater than Arkansas Post.