The main stem of the Andreafsky River and its East Fork are each approximately 125 river miles long. These two portions parallel each other about 10-15 miles apart as they flow south to the Yukon River. The East Fork joins the main Andreafsky River near the village of St. Mary’s, about four miles above the confluence with the Yukon River.
The Andreafsky River is surrounded by the Andreafsky Wilderness except for approximately the lowest 35 river miles where Village Corporation lands border the river. In contrast to the generally low relief of the Yukon Delta region, the Andreafsky and East Fork valleys are bordered by the low, rolling mountains and ridges of the Nulato Hills.
Spruce-hardwood forest extends up the lower three-fourths of the river valley and is one of the western-most stands of spruce in Alaska, a vegetative type that differs markedly from the predominant wet and moist tundra of the region. The upper river areas, as well as the surrounding hills and ridges, are covered by alpine tundra.