Background: Recently, Paggi et al. [Gerontology 2016; 62: 450–458] for the very first time showed in a cross-sectional sample of 259 adults aged 18–81 years that the relation of physical health to psychological well-being was mediated via frequency of leisure activity participation. Objective: To extend this framework, we followed theories on successful aging and vulnerability to propose to add a differential perspective predicting that certain individuals may be more vulnerable than others and therefore may show differences in the mediation pattern. Specifically, we examined whether mediation patterns were differential in certain populations, such as in old-old (compared to young-old) adults and in individuals who carried out a low (compared to those with a high) number of activities. Methods: We analyzed data from 3,080 individuals on physical health (number of chronic diseases, subjective health status, and subjective evaluation of change in health over the last 10 years), frequency of participation in 18 leisure activities, and physical and psychological well-being using moderated mediation models with a path model approach that allowed the simultaneous estimation of all model paths, including their significance. Results: We found that the relation of physical health to physical and psychological well-being was mediated via frequency of activity participation. For physical (but not for psychological) well-being, this mediation was more pronounced in old-old (compared to young-old) adults and in individuals who carried out a low (compared to those with a high) number of activities. These moderated mediations were attributable to differential relations of physical health to frequency of activity participation and to differential relations of frequency of activity participation to physical wellbeing between the investigated moderator levels. Conclusion: Present data suggest that participation in leisure activities may play a key role in mediating the relationship between physical health and well-being, particularly in very old age. Findings are discussed with respect to theories of successful aging and differences between physical and psychological well-being.