The waters of Lake Clark National Park and Preserve feed two major watersheds. Some lakes and rivers in the north part of the park are part of the Kuskokwim watershed. The Necons and Telaquana rivers flow into the Stony River, which runs west and joins the mighty Kuskokwim River.

Most of the park's waters, though, are part of the Kvichak watershed. These lakes and rivers flow into Lake Clark, which in turn enters Iliamna Lake via the Newhalen River. Iliamna Lake flows into Bristol Bay via the Kvichak River.

The Kvichak watershed is the world's most productive spawning and rearing habitat for economically important sockeye salmon. About 50% of the sockeye salmon caught in Bristol Bay spawn in its lakes and rivers. This represents 33% of the entire U.S. catch, and 16% of the total world catch. One of the primary reasons Lake Clark National Park and Preserve was established was to protect a portion of the Bristol Bay watershed for the perpetuation of the sockeye salmon fishery. By protecting these waters, NPS helps sustain the Alaskan economy and culture.