Archaeological evidence from a nearby site indicated that the area around Kwethluk has been occupied since prehistoric times. The community is located on the Kwethluk River at its junction with the
Kuskokwim River.
Gold mining took place in nearby creeks in the early 1900s. One placer deposit, discovered on the upper Kwethluk River, was worked until WWII. At one time, the villagers owned over 30,000 reindeer.
Today, seal meat and seal oil are obtained in trade with coastal relatives and neighbors. Salmon, moose, and caribou are the staples of the diet in Kwethluk.