[1] The name of the river comes from the Okanagan placename [txwə́c’p],[2] perhaps meaning "wasp" or "yellowjacket".

[3] The Twisp River originates in the North Cascades portion of the Cascade Range.

Flowing generally east, 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).

The Twisp River flows into the Methow River at the town of Twisp, Washington.

A Japanese incendiary balloon was reported on the Twisp River in 1945.