<h3>Importance</h3> Diseases of despair (ie, mortality or morbidity from suicidality, drug abuse, and alcoholism) were first characterized as increasing in rural White working-class populations in midlife with low educational attainment and associated with long-term economic decline. Excess mortality now appears to be associated with working-class citizens across demographic and geographic boundaries, but no known qualitative studies have engaged residents of rural and urban locales with high prevalence of diseases of despair to learn their perspectives. <h3>Objective</h3> To explore perceptions about despair-related illness and potential intervention strategies among diverse community members residing in discrete rural and urban hotspots. <h3>Design, Setting, and Participants</h3> In this qualitative study, high-prevalence hotspots for diseases of despair were identified from health insurance claims data in Central Pennsylvania. Four focus groups were conducted with 60 community members in organizations and coalitions from 3 census block group hotspot clusters in the health system between September 2019 and January 2020. Focus groups explored awareness and beliefs about causation and potential intervention strategies. <h3>Main Outcomes and Measures</h3> A descriptive phenomenological approach was applied to thematic analysis, and a preliminary conceptual model was constructed to describe how various factors may be associated with perpetuating despair and with public health. <h3>Results</h3> In total, 60 adult community members participated in 4 focus groups (44 women, 16 men; 40 White non-Hispanic, 17 Black, and 3 Hispanic/Latino members). Three focus groups with 43 members were held in rural areas with high prevalence of diseases of despair, and 1 focus group with 17 members in a high-prevalence urban area. Four themes emerged with respect to awareness and believed causation of despair-related illness, and participants identified common associated factors, including financial distress, lack of critical infrastructure and social services, deteriorating sense of community, and family fragmentation. Intervention strategies focused around 2 themes: (1) building resilience to despair through better community and organizational coordination and peer support at the local level and (2) encouraging broader state investments in social services and infrastructure to mitigate despair-related illness. <h3>Conclusions and Relevance</h3> In this qualitative study, rural and urban community members identified common factors associated with diseases of despair, highlighting the association between long-term political and economic decline and public health and a need for both community- and state-level solutions to address despair. Health care systems participating in addressing community health needs may improve processes to screen for despair (eg, social history taking) and codesign primary, secondary, and tertiary interventions aimed at addressing factors associated with distress. Such actions have taken on greater urgency with the COVID-19 pandemic.