Introduction: Previous studies have shown that formal social participation may reduce the risk of developing chronic conditions. Yet, the underlying mechanisms are largely unknown. In this study, we assessed the potential mediating roles of quality of life and depressive symptoms using longitudinal data. Method: We analyzed nationally representative data from three consecutive waves (2011, 2013, 2015) of the SHARE survey, including 28,982 adults from 12 European countries aged 50 years and above at baseline. Measures were self-reported and included formal social participation (i.e. active participation within volunteer organizations, educational institutions, clubs, religious organizations, or political/civic groups), quality of life (CASP-12), depressive symptoms (EURO-D), and chronic conditions. Structural equation modeling was used to construct a focused longitudinal path model. Results: Formal social participation at baseline was inversely associated with the number of chronic conditions at 4-year follow-up. We identified two significant longitudinal mediation patterns: 1) formal social participation predicted higher levels of quality of life, which in turn, predicted lower levels of chronic conditions; and 2) formal social participation predicted lower levels of depressive symptoms, which, in turn, also predicted lower levels of chronic conditions. Conclusions: Formal social participation functions as a protective factor against the onset or development of chronic conditions. This association is partially explained by enhanced quality of life and diminished depressive symptoms.