The Sixes River flows about 31 miles (50 km) through coastal forests in southwestern Oregon in the United States.

It flows generally west, through Grassy Knob Wilderness and the small community of Sixes, and eventually enters the Pacific just north of Cape Blanco, the westernmost point in Oregon.

Hodge's Handbook of American Indians says that one of the variants of the name of the local tribe, the Kwatami (a subdivision of the Tututni), was "Sik-ses-tene", which is said to mean "people by the far north country".

Though this is most likely the real source of the name, the spelling "Sixes" was probably used by miners drawn to the Oregon gold rush who were familiar with the Chinook word "sikhs".

Wildlife species include salmon, steelhead, coastal cutthroat trout, marbled murrelets, northern spotted owls, and Roosevelt elk, among others.