The interior Alaskan region experiences extremes of weather, with temperatures that can vary from −50 °F (−46 °C) in winter to 97 °F (36 °C) in summertime.

Today the preserve includes part of the route of the annual Yukon Quest dogsled race, which runs every February.

[3] The northern part of the preserve includes a portion of the Yukon River valley, which runs from east to west after entering Alaska from Canada near Eagle.

The southern portion of the preserve includes the entire drainage of the Charley River, one of the Yukon's tributaries.

Summer nights in June and early July do not get fully dark, owing to the preserve's location close to the Arctic Circle.

Hot summer temperatures and dry weather allow lightning strikes to start fires which maintain a diverse ecosystem.

The chief salmon species in the portion of the Yukon that runs in the preserve are chinook, coho and chum.

Large mammals in the preserve include wolf, black bear, moose, caribou, and Dall's sheep.

Evidence from other portions of northern Alaska indicates that people lived in the area as early as 11,000 years before the present.

One theory proposes that the eruption of the White River Ash about 1900 years ago from Mount Churchill in the Saint Elias Mountains displaced people from the region of Kluane Lake into the relatively ash-free Yukon valley.

[6] The inhabitants of the upper Yukon valley just prior to historic times were the Hän people, descendants of the Athabaskan migrants.

[17] Yukon-Charley Rivers National Monument was proclaimed on December 1, 1978, by President Jimmy Carter using his authority under the Antiquities Act.

Carter took the action after the Alaska National Interest Lands Conservation Act (ANILCA) was held up in Congress.

In 1980 ANILCA was passed, and was signed into law by Carter on December 2, 1980, converting the monument into a national preserve.