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Introduction: Appalachian residents are more likely than other populations to have Type 2 Diabetes Mellitus (T2DM) and to experience more severe complications from the disease, including excess and premature mortality., Methods: This study examines health alongside sociodemographic factors, psychosocial factors (including knowledge, empowerment, social support/function, religiosity, distress), and perceived problems in diabetes management that may influence self-care and HbA1c among vulnerable rural residents. A survey of a community-based sample of 356 adults with diagnosed diabetes or HbA1c > 6.5 was conducted in six counties in Appalachian Kentucky., Results: Findings suggest that neither religiosity nor social support/function mediate/moderate the relationship between psychosocial factors and dependent variables (problem areas in diabetes, T2DM self-care or HbA1c). Results also suggest that distress is a predictor of problem areas in diabetes, and both distress and empowerment are predictors of T2DM self-care., Implications: This study addresses the gap in the literature concerning the influence of psychosocial factors on problem areas in diabetes, T2DM self-care and HbA1c among vulnerable rural residents, as well as the potential mediating/modifying effects of religiosity and social function/support. Future research is needed to inform strategies for identifying and addressing distress among vulnerable populations burdened by T2DM, including Appalachian adults., Competing Interests: No competing financial or editorial interests were reported by the authors of this paper., (Copyright © 2023 Brittany L. Smalls, Md. Tofial Azam, Madeline Dunfee, Philip M. Westgate, Susan C. Westneat, and Nancy Schoenberg.)