This study aimed to evaluate the possible mediating role of psychological flexibility in the association between fear of COVID-19, affective symptoms and well-being. 403 subjects were recruited; fear of COVID-19, psychological flexibility, affective symptoms and well-being were assessed via self-report measures. Correlation and mediation analyses were run. Psychological flexibility was found to play a mediating role in the association between fear of COVID-19 and more severe affective symptoms (adjusted R-squared = 52%, p < 0.001), and between fear of COVID-19 and poor well-being (adjusted R-squared = 41%, p < 0.001). Psychological flexibility may mitigate the negative impacts of fear of COVID-19 on affective symptoms and well-being Psychological flexibility could be the potential therapeutic target in clinical interventions aimed at reducing the adverse effects of fear of COVID-19 on mental health.