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Named for nearby Cherokee Creek, the community was established in the early 1850s, when P.P. "Pop" Woodard settled at a site five miles west of the present location. A post office opened in 1858 and changed its location several times before ending up in James Samuel Hart's store in July 1879. The permanent town site was laid out by David Seth Hanna in 1878. The community had an estimated population of 500 by the mid-1890s and supported several businesses. Cherokee became a county center of higher education when Francis Marion Behrns established the Cherokee Academy in 1894. Two years later, the name was changed to West Texas Normal and Business College. A building that originally belonged to the college was purchased from Behrns on April 4, 1911 to house Cherokee Junior College. In 1921, it was sold to the county school district to serve as a high school. The community had population was approximately 250 during the 1920s. Cherokee High School's main building was destroyed in a 1945 fire. It was rebuilt using the original facade. With no rail connection, Cherokee remained small and the number of residents held steady at around 250 throughout most of the twentieth century. That figure had fallen to 175 by 1990 and remained at that level in 2000.
Today, the community has a post office (zip code: 76832), a general store, and a volunteer fire department. Ranching and hunting are the primary business activities in the area. During the fall, seasonal hunting brings in additional revenue that supports fuel stations, a hardware store, and a feed store as well as taxidermy and restaurant operations. The Cherokee Home for Children, a basic-care residential children's facility is located just north of the community.
Public education in the community of Cherokee is provided by the Cherokee Independent School District. The district has one campus, Cherokee School, that serves students in grades kindergarten through twelve.