Psychological resilience (PR) is the capacity to adapt positively in face of adversity. Its role as an independent protective factor has been acknowledged in recent years. We aimed to test the association of PR with all-cause and cardiovascular disease (CVD) mortality in a general adult population. We performed longitudinal analyses on 10,406 CVD-free individuals from the Moli-Sani cohort (follow up = 11.2 year). PR was assessed by the 25-item Connor and Davidson resilience scale. PR factors were identified through polychoric factor analysis. Associations with mortality were tested using multivariable Cox regressions. Higher levels of PR were associated with reduced all-cause mortality in a model including sex and age (HR = 0.78; 95%CI 0.62–1.00). The association decreased after inclusion of socioeconomic, clinical, and behavioral factors into the model (HR = 0.80; 95%CI 0.62–1.03). No relation was observed with cardiovascular mortality in the fully adjusted model (HR = 0.89; 95%CI 0.56–1.39). An inverse association of Factor 1 (reflecting positive acceptance of change) with all-cause mortality (HR = 0.89; 95%CI 0.82–0.98; p value = 0.01) was found. However, at a borderline non-significant way, PR predicts all-cause mortality in a general population of Italian adults. This is supported by the findings demonstrating a significant association between the PR’s domain reflecting a positive acceptance of change and all-cause mortality.