The COVID-19 pandemic involved a complex set of stressors affecting the health and well-being of the population. The understanding of the psychological processes that influence well-being in response to the pandemic and their interrelation is vital. A promising process in understanding the emotional impacts of these stressors is psychological flexibility. This study investigated the effect of psychological flexibility on well-being, both directly and indirectly, via mindfulness and coping strategies. A total of 334 Portuguese adults participated in this cross-sectional study. Participants were asked to complete an online questionnaire, including measures of psychological flexibility, well-being, mindfulness, and coping strategies. A multiple mediation model studied whether there are conditional indirect effects of mindfulness and coping strategies on well-being. The results showed statistically significant correlations between psychological flexibility, well-being, mindfulness, and coping strategies. Furthermore, we found that mindfulness and coping strategies partly mediate the relationship between psychological flexibility and well-being. Understanding the processes through which psychological flexibility influences well-being in a stressful context is important in comprehending the processes involved in an emotional reaction to a pandemic-like societal event. Mindfulness and coping are shown to be important processes to consider in understanding this phenomenon and designing future responses.