Background: Since the onset of the pandemic, COVID-19 mortality has disproportionately impacted populations impacted by health inequities. This study aimed to identify the barriers and facilitators to COVID-19 vaccination uptake in Appalachian Kentucky as a first step to developing vaccination interventions. Methods: Key informant interviews were conducted with 36 community leaders in 14 Appalachian Kentucky counties from January-June 2023. Interviews focused on leaders’ perspectives about their community’s COVID-19 experiences, community impacts of the pandemic, and vaccine facilitators and barriers in their communities. Iterative inductive-deductive coding was used to characterize responses. Results: There were barriers and facilitators at multiple levels of the socioecological model. For example, individual barriers included distrust of federal government and diminished perceived risk, and interpersonal barriers included anti-vaccination norms. Community barriers included logistical challenges, as well anti-vaccination messages from healthcare providers. Perceived politicization of the vaccine and frequent changes to recommendations during the pandemic presented policy-level barriers. Facilitating factors included pro-vaccine messages from trusted community leaders, beliefs about reducing risk for others, and cues to action such as community events. Conclusions: The challenges to and opportunities for improving COVID-19 vaccination uptake identified here can inform vaccination education, distribution, and policy efforts in both Appalachian Kentucky and other communities with similar characteristics.