Family and social support can enhance our perception of our ability to cope with stressful life events, as well as our psychological flexibility and mental well-being. The main goal of this unique study was to explore how a complex interplay of family, social, and personal factors contribute to mental well-being and life satisfaction. We hypothesized that differentiation of self (DoS) and social support (from family, friends, and significant others) would be positively associated with mental well-being and life satisfaction through the mediation of resilience. The sample included 460 participants (mean age 45.2; 236 males), who filled out questionnaires examining DoS, social support, resilience, mental well-being, and life satisfaction. In light of gender disparities evident in both existing literature and the current study, we analyzed the model separately for women and men. The findings revealed a mediation model, indicating that resilience mediated the relationship between two dimensions of DoS (emotional reactivity and I-position) and mental well-being for males, while DoS and social support contributed to women’s mental well-being without the mediation of resilience. Two factors emerged as contributors to improved mental well-being and life satisfaction: DoS and social support. Specifically, DoS was deemed important for both men and women, while social support emerged as a crucial dimension mainly for women.