It drains a mountainous area of 1,660 square miles (4,300 km2) consisting primarily of low rolling foothills intersected by small streams south and east of Hells Canyon along the Idaho-Oregon border.

It rises in northern Adams County in the Seven Devils Mountains, approximately 10 miles (16 km) west of New Meadows in the Payette National Forest.

In southern Washington County it turns west for its lower 10 miles (16 km) and enters a broadening valley called the Weiser Cove along the northwestern extreme of the Snake River Plain before entering the Snake from the east at Weiser.

For much of its upper reaches, the river follows a narrow course through the mountains, emerging at times into several broad ranching valleys, including one around Midvale.

Although it flows unimpeded, it is used for irrigation in the vicinity of its mouth upstream from Weiser, as well along tributaries in its upper reaches.