This qualitative case study uses a life-course approach to explore syndemic vulnerability in a former fishing village in the Netherlands. Building on four years of fieldwork in a low-income neighborhood, we explored salient themes between and across families and generations. Elderly community members (>65 years) were interviewed to map village history and explore how contextual factors have affected family life, health, and wellbeing since the 1940s. We systematically traced and compared processes leading to or from syndemic vulnerability by studying seven families across three generations. Adults with at least one of clustering diseases, their parents (when possible), and their children participated in semi-structured life-course interviews.A complex interaction of endemic social conditions, sociocultural normative processes, learned health behaviors, and disheartening life events shaped families’ predispositions for a syndemic of psychological distress, cardiometabolic conditions, and musculoskeletal pain. Educational attainment, continued social support, and aspirational capabilities emerged as themes related to decreasing syndemic vulnerability.This study demonstrates that syndemic vulnerability is potentially intergenerational and reveals the need for culturally sensitive and family-focused syndemic interventions. Future longitudinal research should focus on unravelling the pathogenesis of the clustering of psychological distress, cardiometabolic conditions, and musculoskeletal pain among young people.