Lost River begins and ends in a closed basin in northern California and southern Oregon in the United States.

[4] From its source, the river flows into Langell Valley, where Miller Creek enters from the right.

Near Bonanza, the river turns west and passes through Olene Gap, about 10 mi (16 km) east of Klamath Falls.

[6] Dams, canals, pumps, and other artificial structures on the Lost River, Clear Lake, and Tule Lake are part of the Klamath Project of the U.S. Bureau of Reclamation, which manages the basin's water flow mainly for farming and flood control.

[7] After 1846, the Applegate Trail crossed the river on a natural bridge of stepping-stones, later covered by a Bureau of Reclamation dam, near Merrill.