The reservoir behind Wells Dam, into which the Okanogan empties, is called Lake Pateros.

Early maps of the fur trade era show the Okanagan River as the "Caledonia River", a name conferred as it was the connecting route between the Columbia District and the New Caledonia Fur District (which began north of Okanagan Lake).

Fort Okanogan, a fur-trading post opened by the Pacific Fur Company (PFC) late in 1811, was located at the river's confluence with the Columbia.

The isolation and pressures caused by the War of 1812 forced the PFC to sell its property and assets to its Canadian rivals, the North West Company.

During the Fraser Canyon Gold Rush of 1858–1859, parties of armed miners, often at conflict with native peoples in the region, traveled the Okanagan Trail and its western branch, the Similkameen Trail, via the river.