[8] The main stem of the river is lined by the communities of Evansville, Bettles, Alatna, Allakaket, Hughes, and Huslia before reaching Koyukuk.

[11][12][13] The Western Union Telegraph Expedition used the spelling of Coyukuk before the United States Board on Geographic Names settled on Koyukuk.

Vegetation along the Koyukuk River, sparse along the upper reaches, consists of tundra plants such as dwarf willows and other shrubs, sedges, and lichens.

Trees found in more well-drained areas along the river include mountain alder, trembling aspen, white, and black spruce.

[7] Other major vertebrates in the region include bald eagles, brown and black bears, mink, beaver, marten, and river otter.

[7] Moose herds, which thrive in parts of the watershed, especially in riparian zones downstream of Hughes, attract local and non-local hunters, bears, and wolves.