Except for its headwaters in the mountains, the river is broad and flat for its entire course, making it a useful transportation route for many types of watercraft, as well as road vehicles during the winter when it is frozen over.

The South Fork (200 mi/320 km) rises in the southwestern end of the Alaska Range west of Mount Gerdine and flows north-northwest through the mountains, past Nikolai, receiving other streams that descend from the Alaska Range northwest of Denali.

It passes a series of Yup'ik villages, including Aniak, and approaches within 50 mi (80 km) of the Yukon before diverging southwest.

The lower river below Aniak is located within the Yukon Delta National Wildlife Refuge.

It receives the Swift, Stony, and Holitna rivers from the south at the southern end of the Kuskokwim Mountains before emerging on the coastal plain.

Approximately 20 miles (32 km) upstream from Bethel it receives the Kisaralik and Kwethluk rivers from the south.