The river was named after the Methow Native Americans (today part of the Confederated Tribes of the Colville Indian Reservation). The name "Methow" comes from the Okanagan placename /mətxʷú/, meaning "sunflower (seeds)". The Native American name for the river was Buttlemuleemauch, meaning "salmon falls river". In 1841 the Wilkes Expedition named the river "Barrier River". Alexander Rosssaid the native name was Buttle-mule-emauch. In 1811 David Thompson met the tribe living along the river and wrote their name as Smeetheowe. In 1853 George Gibbs called the river Methow or Barrier.
The Methow River, along with its tributaries the Twisp River, Cedar Creek, and Early Winters Creek, originates in a cluster of high mountains including Golden Horn, Tower Mountain, Cutthroat Peak, Snagtooth Ridge, Kangaroo Ridge, Early Winter Spires, and Liberty Bell Mountain. Several mountain passes are associated with the Methow River and its tributaries, such as Methow Pass and Twisp Pass. State Route 20 utilizes Washington Pass and Rainy Pass, also in the general areas of headwater streams. At the source, the river is 5,677 feet above sea level.
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 Mount 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. As the Methow reaches the mouth, it has dropped to an elevation of 784 feet above sea level and has travelled 80 miles.