The river originates at Nenana Glacier in the Alaska Range and includes many whitewater rapids before joining the shallower, slow-moving Tanana River at the town of Nenana.  The Nenana River serves as a hub for barge operations, serving communities up and down the Yukon River and connecting waterways for hundreds of miles.

The Parks Highway crosses the river several times and runs parallel to it between Cantwell and Nenana. The river forms the eastern boundary of the Denali National Park and Preserve and becomes very spectacular at this point.

It is also here where the Nenana Ice Classic takes place. Bets are made on the exact day and time the river ice will break up. The winnings exceed $300,000 and is usually split between multiple contestants.