Native Americans had been living on the Coosa Valley for millennia before Hernando de Soto and his men became the first Europeans to visit it in 1540.

The French had traveled from there upriver and believed that the Coosa River was a key gateway to the entire South; they wanted to control the valley.

In the early 18th century, almost all European and Indian trade in the southeast ceased during the tribal uprisings brought on by the Yamasee War against the Carolinas.

Afterward, the Treaty of Fort Jackson in 1814 forced the Creek to cede a large amount of land to the United States, but left them a reserve between the Coosa and Tallapoosa rivers in northern Alabama.

The Cherokee capital city of New Echota was located on the headwater tributaries of the Coosa River, in Georgia, until the tribe's removal.

So successful were their pioneering efforts,[example needed] that the Medical Division of the League of Nations visited Alabama to study the new methods during the construction of Mitchell Dam.

[6] For a time, the Popeye the Sailorman cartoons were inspired by Tom Sims, a Coosa River resident of Rome, Georgia.

[7] The following table describes the seven impoundments on the Coosa River from the south to north built by the Alabama Power Company as well as the tailwater section below Jordan Dam.

Ten conservation targets were chosen: the riverine system, matrix forest communities (oak hickory-pine forest), gray bat (Myotis grisescens), riparian vegetation, mountain longleaf pine (Pinus palustris) forest communities, red-cockaded woodpecker (Picoides borealis), critically imperiled aquatic species (fish, mussels, and snails), southern hognose snake (Heterodon simus), caddisflies, and imperiled plants.

Maintaining the biodiversity of the Coosa River system is particularly important because it has already lost a significant portion of its aquatic fauna to extinction.

[21] The upper Coosa watershed in northeastern Alabama and north Georgia is home to the majority of the remaining clumps of the endangered green pitcherplant.

[23] The bald eagle, once an endangered species now has nesting populations on and in the vicinity of Coosa River impoundments[25] The largest concentration of clusters in Alabama of the red-cockaded woodpecker, an endangered species, occurs on lands adjacent to Lake Mitchell under the stewardship of Alabama Power.