The 3.5 million-acre Koyukuk National Wildlife Refuge lies within the floodplain of the Koyukuk River, in a basin that extends from the Yukon River to the Purcell Mountains and the foothills of the Brooks Range. This region of wetlands is home to fish, waterfowl, beaver and moose, and wooded lowlands where bears, wolves, lynx and marten prowl. The 750,000-acre Northern Innoko National Wildlife Refuge, commonly known as Kaiyuh Flats, is managed as part of the Koyukuk/Nowitna Refuge Complex. Rich in wetlands, the Northern Innoko is an extremely productive breeding area for migratory waterfowl and fish. The streams and rivers of the refuge complex support three species of salmon, arctic grayling, sheefish, and many other fish species. Northern pike, especially those that winter in the shallow lakes of the Northern Innoko National Wildlife Refuge, sometimes grow to record size. In the Koyukuk's wetlands, breeding waterfowl feast upon water plants and abundant protein-rich invertebrates. Young birds grow quickly in the short, lush summer, and prepare for the fall migration. As many as 100,000 ducks are hatched and raised on Refuge lands during a single nesting season. Migratory songbirds and raptors also depend on the rich resources of the Koyukuk Refuge for breeding and raising young. Koyukuk Refuge's Three-Day Slough area, part of the 400,000 acre Koyukuk Wilderness, has some of the most productive moose habitat in Alaska. This region has, at times, supported more than 10 moose per square mile. Recent counts indicate that some areas still contain densities of five moose or more per square mile. As with much of the refuge big game work, these moose counts are cooperative efforts between the U.S. Fish and Wildlife Service and Alaska Department of Fish and Game. Caribou from the migratory Western Arctic Herd, which numbers more than 450,000, often move into the northernmost reaches of the Refuge in winter months in search of lichens that lie beneath the snow. The Koyukuk also supports a resident non-migratory caribou population, the Galena Mountain Herd, which numbers about 300. Wolves, lynx and other furbearers, as well as black and grizzly bears, are found on the Refuge year around.

The Koyukuk and Northern Innoko Refuges are part of the vast roadless region that makes up much of northern and western Alaska. Traversing the Koyukuk and Kaiyuh takes two days by motor boat and more than an hour in a small airplane. Commuter aircraft provide regularly scheduled air transportation from Fairbanks and Anchorage to Galena, where the Refuge headquarters is located. Visitors can charter small aircraft for travel to the Refuge from Galena. The Koyukuk River is a major tributary of the Yukon River, and some visitors, mostly moose hunters, use the river to enter the Refuge by boat. The Koyukuk River mouth is approximately 312 miles downriver from the Dalton Highway Bridge on the Yukon River or the Tanana River Bridge at Nenana. Local residents travel extensively on the Yukon and Koyukuk Rivers, by boat in the summer and snow machine in the winter.