[1] The lower river course, to a point north of Manila Creek, were notably marked by cyclical inundation from Glacial Lake Columbia over a period of at least 900 years during the Fraser Glaciation.

Several ore mills were in operation on or near tributaries of the Sanpoil, using mercury plate amalgamation and MacArthur-Forrest cyanide leaching processes.

Before construction of the hydroelectric dams on the Columbia River, notably Grand Coulee Dam in 1941, the Sanpoil basin hosted runs of anadromous salmon and Steelhead trout, along with Pacific lamprey, but the runs have gone extinct due to the lack of a fish ladder at Grand Coulee.

In August 2019 100 "naive adult" Chinook salmon were released in three groups into the Sanpoil River by the Colville Tribal Fish and Wildlife Department.

This was an effort to begin repopulation of the species almost 70 years after the historic runs were killed by completion of Grand Coulee Dam.

[10] The salmon were born and raised in the Wells fish hatchery, and do not have a instinctual connection to a specific stream or river for spawning.

A single native minnow, the redside shiner, burbot, three species of sculpin, the mottled, paiute, and prickly, and a landlocked white sturgeon population are all part of the fish fauna.

[1] There are also a number of introduced fish species that have populations in the river, including the salominds brook and brown trout, the lake whitefish, the cyprinid common carp and the tench.

[1] Relatively low numbers of adfluvial wild rainbow trout and hatchery-released kokanee salmon return to the Sanpoil River from Lake Roosevelt.

Smallmouth bass and walleye, two nonindigenous predators that stage at the river/lake interface during the juvenile migration season, are thought to consume large numbers of these species.

The pair were caught before the female could spawn, but there is concern that the encroachment could impact native runs of redband and bull trout.

[13] The river valley is the hereditary home of the Sanpoil people, the Interior Salish who are now part of the Colville Confederated Tribes.

[18] On January 2, 1902, the Spokane and British Columbia Railway was approved by the Secretary of the Interior to conduct surveying for a southern line though the Colville Reservation along the Sanpoil River.

[21] In early 2017, heavy rains combined with intense snowmelt throughout the Sanpoil River Basin resulted in the worst flooding that had been seen in the valley in decades.