Nenana is in the westernmost portion of Tanana Athabascan Indian territory. It was first known as Tortella, an interpretation of the Indian word "Toghotthele."

The Athabascan word Nenana means "a good place to camp between the rivers."  Jim Duke constructed a trading post/roadhouse there in 1903 to supply river travelers and promote trade with the Athabascans.

In 1905, St. Mark's Episcopal Mission was built upriver. It, as well as the Railroad Depot, are on the National Register of Historic Places. The log church has hand-carved pews and an altar covered with Native beadwork done on moosehide.