The river was named after the Methow Indian Tribe (today part of the Confederated Tribes of the Colville Indian Reservation). The Indian name for the river was Buttlemuleemauch, meaning "salmon falls river".
The Pacific Crest Trail follows the uppermost reach of the Methow River, until the river turns east, flowing into the Methow Valley near Mazama. Along the way it collects the tributary streams of Robinson Creek and Lost River. In the Methow Valley, between Mazama and Winthrop, the Methow River is joined by Early Winters Creek, Cedar Creek, Goat Creek, and Wolf Creek. The Chewuch River joins at Winthrop. One of the Methow's larger tributaries, the Chewuch River and its many tributaries drain large parts of the Pasayten Wilderness to the north. One of its headwater streams, Cathedral Creek, reaches nearly to British Columbia, Canada.
The Methow Valley continues below Winthrop to Twisp, where the Methow River is joined by another important tributary, the Twisp River. Flowing from the west, the Twisp River drains the mountains south of Washington Pass as well as the eastern slopes of Sawtooth Ridge, a major mountain range with some of Washington state's highest peaks (such as Star Peak and Mt Bigelow).
Downriver from Twisp, the Methow River passes by the communities of Carlton and Methow, receiving several minor tributaries, before joining the Columbia River at Pateros. This part of the Columbia is the impoundment of Wells Dam, a lake known as Lake Pateros.