Cantwell is named after Lieutenant J. C. Cantwell, military explorer and commander of the revenue steamer Corwin on the Yukon River, 1898-1900. Prior to the settlement, the only inhabitants of the Cantwell area were nomadic Tanana Indians and Athabascan Native Alaskans who hunted and fished. In their language they named Cantwell Yede'teni'na. The town began as a flag stop on the Alaska Railroad. This flagstop supplied the Valdez Creek mining area, which had the name "Denali" for the Valdez Creek community. Many Indians from the village of Tyone came to work at Valdez Creek and later lived out their lives in the Cantwell area. Many Tyones are buried in the old Cantwell graveyard, next to the railroad tracks. Oley Nicklie, a Native Alaskan, sought work with the railroad after fur prices dropped. He and his two brothers then founded part of the settlement. Cantwell is 20 miles away from a giant abandoned igloo shaped hotel, which is not made out of ice. Cantwell served as a partial filming location for the Lure of the Yukon during the 1920s, and for the 2007 movie Into the Wild.
Cantwell first appeared on the 1940 U.S. Census as an unincorporated village. It was classified as a census-designated place in 1980. As of the census of 2000, there were 222 people, 102 households, and 59 families residing in the CDP. The population density was 1.9 people per square mile. There were 178 housing units at an average density of 1.5/sq mi. The racial makeup of the CDP was 65.32% White, 0.45% Black or African American, 22.52% Native American, 1.80% Asian, 0.90% from other races, and 9.01% from two or more races. Hispanic or Latino of any race were 1.35% of the population. There were 102 households, out of which 25.5% had children under the age of 18 living with them, 44.1% were married couplesliving together, 8.8% had a female householder with no husband present, and 41.2% were non-families. 33.3% of all households were made up of individuals, and 2.9% had someone living alone who was 65 years of age or older. The average household size was 2.18 and the average family size was 2.80. In the CDP, the population was spread out, with 20.7% under the age of 18, 4.1% from 18 to 24, 37.4% from 25 to 44, 30.2% from 45 to 64, and 7.7% who were 65 years of age or older. The median age was 40 years. For every 100 females there were 111.4 males. For every 100 females age 18 and over, there were 114.6 males. The median income for a household in the CDP was $43,750, and the median income for a family was $39,792. Males had a median income of $55,625 versus $17,500 for females. The per capita income for the CDP was $22,615. None of the families and about 2.0% of the population were living below the poverty line, including none of those under the age of 18 and none of those 65 and older.
