Talkeetna is situated on the confluence of three wild, glacially fed rivers:
the Susitna, Chulitna, and Talkeetna. An important location for fishing and trading by the Dena'ina, a subset of theAthabaskan people, the village's name comes from the Athabaskan word for river of plenty, K'Dalkitnu.

As early as 1896, a gold rush in the Susitna River area brought prospectors here. Talkeetna was the site for a riverboat steamer station (1915) that brought supplies to prospectors heading northwest to mining claims.

In 1916, Talkeetna was chosen as a divisional headquarters for the Seward to Fairbanks government railroad route, approved by President Woodrow Wilson in 1914. During the railroad's construction, Talkeetna's population peaked near 1,000.

The 1918 Influenza epidemic and 1923 completion of the railroad decreased the town's population. However, it remained a supply center for area miners until 1940 when many of the richest mines' production declined. Talkeetna continued to survive through the years with a combination of miners, trappers, homesteaders, and railroad workers who called this place home. In 1964 Talkeetna connected to the George Parks Highway (Route 3) by the 14 mile Talkeetna Spur road, opening up the area to vehicle access and development.