Dispositional mindfulness and dispositional serenity were found in previous research to complement one another in promoting mental health. Extending this research, the present study investigated the effects of both in relation to mental well-being (MWB) and stress during the COVID pandemic. It also examined whether distinct cognitive emotion regulation (CER) strategies mediated relationships between them and MWB and stress. Using a cross-sectional design, the present study found that mindfulness and serenity incrementally predicted greater MWB and less stress. Furthermore, adaptive and maladaptive CER differentially mediated the relationships between aspects of mindfulness and serenity and both MWB and stress. Among the mindfulness facets, most notably, acting with awareness and nonjudging were only associated with maladaptive CER, which partially mediated their relationship with both MWB and stress. Among the serenity dimensions, adaptive CER and maladaptive CER mediated the relationships between the serenity factors and both MWB and stress. Individuals with high serenity appeared to engage in more meaning-restructuring positive thinking and dwell less on negative thoughts and emotions that helped to promote MWB and reduce stress. In contrast, those who were more mindful seemed to decrease rumination, catastrophizing, and self-blame to promote MWB and reduce stress. Clinical implications of the present findings are discussed.