Objective: Hopelessness is considered a risk factor for several mental and behavioral disorders. Research has shown that a stressful life event can be a significant predictor of hopelessness. The aim of the current research study was to explore the relationship between stressful life events and hopelessness, as well as to analyses the mediation effect of both mentalization and emotional dysregulation on this relationship. Methods: In a cross-sectional design, 607 participants recruited from the Spanish general population completed a series of measures. Results: Hopelessness was significantly related to stressful life events (r = 0.24, p < 0.001), emotion dysregulation variables (r = 0.18/0.38), and most measures of mentalization (r = 0.02/0.34). A good-fitting structural equation modeling-based mediation model (χ2/df = 2.04; root mean squared error of approximation = 0.042 [90%CI 0.033-0.050]; comparative fit index = 0.97; non-normed fit index = 0.97) showed that mentalization significantly mediated the relationship between stressful life events and hopelessness, while emotion dysregulation had no significant mediating effect. Conclusions: These results could have important clinical implications, such as the development of mentalization-based interventions for people living under a large number of stressors.