BackgroundIn mid-March 2020, very few cases of COVID-19 had been confirmed in the Central Blue Ridge Region, an area in Appalachia that includes 47 jurisdictions across northeast Tennessee, western North Carolina, and southwest Virginia. Authors described the emergence of cases and outbreaks in the region between March 18 and June 11, 2020.MethodsData were collected from the health department websites of Tennessee, North Carolina, and Virginia beginning in mid-March for an ongoing set of COVID-19 monitoring projects, including a newsletter for local healthcare providers and a Geographic Information Systems (GIS) dashboard. In Fall 2020, using these databases, authors conducted descriptive and geospatial cluster analyses to examine case incidence and fatalities over space and time.ResultsIn the Central Blue Ridge Region, there were 4432 cases on June 11, or 163.22 cases per 100,000 residents in the region. Multiple days during which a particularly high number of cases were identified in the region were connected to outbreaks reported by local news outlets and health departments. Most of these outbreaks were linked to congregate settings such as schools, long-term care facilities, and food processing facilities.ImplicationsBy examining data available in a largely rural region that includes jurisdictions across three states, authors were able to describe and disseminate information about COVID-19 case incidence and fatalities and identify acute and prolonged local outbreaks. Continuing to follow, interpret, and report accurate and timely COVID-19 case data in regions like this one is vital to residents, businesses, healthcare providers, and policymakers.