The river was named for explorer Joseph Reddeford Walker, a mountain man and experienced scout who is known for establishing a segment of the California Trail.

The West Walker River originates at Tower Lake in Mono County, California, 9,623 ft (2,933 m) above sea level in the Stanislaus National Forest.

It then emerges into Antelope Valley, where some water is diverted to the Topaz Lake reservoir, enters Nevada in Douglas County, and turns northeast.

[5] The East Walker River also begins in Mono County, California, in the Bridgeport Valley, fed by several Sierra streams originating in the Hoover Wilderness, including Buckeye, Robinson, Green, and Virginia creeks.

[5] Below the forks, the Walker River flows initially north through the Mason Valley, past Yerington, into central Lyon County.

It turns sharply to the southeast around the north end of the Wassuk Range, flowing through the Walker River Indian Reservation where it is dammed to create Weber Reservoir.

[8] The U.S. Geological Survey divides the basin into 4 sub-basins: The Walker River headwaters originate along a large section of the Sierra Crest at elevations of 12,000 feet (3,700 m) or more.

[13] Due to a very heavy snowpack in the winter of 1996/1997 and a very warm spring, the West Fork of the Walker River flooded to unprecedented levels.

That North American beaver (Castor canadensis) were once native to the Walker River is evidenced by a 1906 article in the Nevada State Journal newspaper by newspaper mining writer Fitz-James MacCarthy (aka Fitz-Mac), who stated that the Mason's Valley of the Walker River in Yerington was well known to "the early trappers and fur hunters...Kit Carson knew it to the bone...The beavers of course were all trapped long ago, and you never see an elk nowadays..."[14] Beaver have since re-colonized the Walker River watershed.