Human trafficking is an ongoing, global human rights crisis and one of the largest illicit industries worldwide. Although there are thousands of victims identified each year within the United States, the true extent of this problem remains unknown due to the paucity of data. Many victims seek care in the emergency department (ED) while being trafficked but are often not identified by clinicians due to lack of knowledge or misconceptions about trafficking. We present a case of an ED patient being trafficked in Appalachia as an educational stimulus and discuss several unique aspects of trafficking in rural communities, including lack of awareness, prevalence of familial trafficking, high rates of poverty and substance use, cultural differences, and a complex highway network system. The lack of data, appropriate resources, and training for healthcare professionals also poses distinct issues. We propose an approach to identify and treat victims of human trafficking in the ED, with a focus on rural EDs. This approach includes improving data collection and availability on local patterns of trafficking, improving clinician training in identification, and care of victims using trauma-informed techniques. While this case illustrates unique features of human trafficking in the Appalachian region, many of these themes are common to rural areas across the US. Our recommendations emphasize strategies to adapt evidence-based protocols, largely designed in and for urban EDs, to rural settings where clinicians may be less familiar with human trafficking.