The Owyhee River is a tributary of the Snake River located in northern Nevada, southwestern Idaho and southeastern Oregon in the United States. It is 280 miles (450 km) long. The river's drainage basin is 11,049 square miles (28,620 km2) in area, one of the largest subbasins of the Columbia Basin. The mean annual discharge is 995 cubic feet per second (cfs), with a maximum of 50,000 cfs recorded in 1993 and a minimum of 42 cfs in 1954. It 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 1,000 feet (300 m) deep.

Its source is in northeastern Nevada, in northern Elko County, approximately 50 miles (80 km) north of the city of Elko. It flows north along the east side of the Bull Run Mountains, passing through Wild Horse Reservoir and then cutting northeast past the north end of the range. The river runs through the Humboldt National Forest, and then past the communities of Mountain City and Owyhee in the Duck Valley Indian Reservation. It then enters southwestern Idaho, flowing northwest for approximately 50 miles (80 km) across the southwest corner of the state through Owyhee County. It is then joined by the South Fork Owyhee River from the south, approximately 10 miles (16 km) east of the Oregon border. The main tributary of the South Fork is the Little Owyhee River.

It then enters extreme southeast Oregon in southern Malheur County, generally flowing north in a zigzag course west 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".  Passing through the Owyhee Canyon between Big Grassy Mountain and Whitehouse Butte, the river turns north, flowing east of Burns Junction and then west of the Mahogany Mountains, receiving the tributaries of Jordan Creek, Rattlesnake Creek, and Crooked Creek.

The Owyhee River enters the Snake River from the west 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.

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