Yukon-Koyukuk lies within Alaska's interior and stretches for more than 157,121 square miles from the Yukon River to the Canadian Border.

Yukon-Koyukuk lies adjacent to North Slope, Fairbanks North Star, Denali, Bethel, Wade Hampton, Nome and Northwest Arctic.
There are several National Protected Areas including the Arctic National Wildlife Refuge, Gates of the Arctic National Park and Preserve, Innoko National Wildlife Refuge, Kanuti National Wildlife Refuge, Koyukuk National Wildlife Refuge, Selawic National Wildlife Refuge, Yukon-Charley Rivers National Preserve and the Yukon Flats National Wildlife Refuge.