It has its source in a narrow valley in the southern margin of the Kigluaik Mountains, 4.5 miles (7.2 km) west of Salmon Lake.

The point where Buffalo and Deep Canyon creeks join, which is regarded as its head, is 26 miles (42 km) north of Nome.

Its valley is wide and is floored with a deep filling of gravels into which the river channel is incised to a depth ranging from 5 to 50 feet (1.5 to 15.2 m).

Hobson Creek joins Nome River about 10 miles (16 km) from the sea; it has a narrow valley and a southerly course.

Dorothy Creek is a tributary to the upper part of Nome River; it flows through a small canyon having a general northerly course.