The refuge was established in 1980 by the Alaska National Interest Lands Conservation Act.

[2] The northern part of the refuge, called Kaiyuh Flats, is adjacent to the Yukon River southwest of Galena.

The southern part contains approximately 3,099,000 acres (12,540 km2) of land surrounding the Innoko River.

The land is swampy and is the nesting area for hundreds of thousands of birds including ospreys, northern hawk-owls, trumpeter swans, bald eagles, common ravens, short-eared owls, and red-tailed hawks.

Mammalian species that habitat this refuge are brown and black bears, moose, wolves, Canadian lynx, marten, porcupine, beaver, caribou, river otter, red fox, wolverine, muskrat, and mink.