While many studies have found positive correlations between greenness and human health, rural Central Appalachia is an exception. The region has high greenness levels but poor health. The purpose of this commentary is to provide a possible explanation for this paradox: three sets of factors overwhelming or attenuating the health benefits of greenness. These include environmental (e.g., steep typography and limited access to green space used for outdoor recreation), social (e.g., chronic poverty, declining coal industry, and limited access to healthcare), and psychological and behavioral factors (e.g., perceptions about health behaviors, healthcare, and greenness). The influence of these factors on the expected health benefits of greenness should be considered as working hypotheses for future research. Policymakers and public health officials need to ensure that greenness-based interventions account for contextual factors and other determinants of health to ensure these interventions have the expected health benefits.