The Owyhee drains a remote area of the arid plateau region on the north edge of the Great Basin, rising in northeastern Nevada and flowing generally northward near the Oregon-Idaho border to the Snake River. Its watershed is very sparsely populated. The Owyhee River and tributaries flow through the Owyhee Plateau, cutting deep canyons, often with vertical walls and in some places over deep.
The Owyhee River then enters extreme southeast Oregon in southern Malheur County, generally flowing north in a zigzag course east of the Idaho border. It merges with the West Little Owyhee River from the south, then receives the Middle Fork Owyhee River and North Fork Owyhee River from the east at a location known as "Three Forks". It then passes through the Owyhee Canyon between Big Grassy Mountain and Whitehouse Butte, then turns north, flowing east of Burns Junction and then west of the Mahogany Mountains. In this area the Owyhee River receives the tributaries of Jordan Creek, Rattlesnake Creek, and Crooked Creek.
The Owyhee River enters the Snake River from the east on the Oregon-Idaho border approximately 5 miles (8 km) south of Nyssa, Oregon and 2 miles (3 km) south of the mouth of the Boise River. The final stretch of the river, below Owyhee Dam, emerges from the Owyhee Plateau and enters the Snake River Plain.
The name of the river is from the older spelling of "Hawaii". It was named for three Hawaiian trappers, in the employ of the North West Company, who were sent to explore the uncharted river. They failed to return to the rendezvous near the Boise River and were never seen again. Due to this the river and its region was named "Owyhee". About one-third of the men with Donald MacKenzie's Snake Country Expeditions of 1819-20 were Hawaiians, commonly called "Kanakas" or "Sandwich Islanders" in those days, with "Owyhee" being a standard period spelling of the proper Hawaiian language name for the islands, hawai'i, which then was otherwise unused in English. The three Kanakas were detached to trap on the river in 1819 and were probably killed by Indians that year. It was not until the spring or early summer of 1820 that MacKenzie learned the news of their deaths (probably at the hands of men belonging to a band of Bannocks led by a chief named The Horse). Indians led other trappers to the site, but only one skeleton was located. The earliest surviving record of the name is found on a map dating to 1825, drawn by William Kittson (who was previously with Donald MacKenzie in 1819-1820, and then with Peter Skene Ogden in 1825), on which he notes "Owhyhee River" [sic]. Journal entries in 1826 by Peter Skene Ogden, a fur trapper who led subsequent Snake Country Expeditions for the Hudson's Bay Company refer to the river primarily as the "Sandwich Island River", but also as "S.I. River", "River Owyhee" and "Owyhee River.
The discovery of gold and silver in the region in 1863 resulted in a temporary influx of miners and the establishment of mining camps, most of whom have long since disappeared. The initial discovery was along Jordan Creek, and mining activity rapidly spread through the Owyhee watershed. The mining effort involved more than placer operations, but underground mines and mills, resulting in a prolonged history of mining in the region.