The COVID-19 pandemic has significantly affected the mental health of the general population worldwide. The study aimed to determine the associations of the intolerance of uncertainty (IU) and cognitive flexibility (CF) with a variety of psychological symptoms and to examine the impact of IU on psychological symptoms through the moderating role of CF. The Brief Symptom Inventory, Intolerance of Uncertainty Scale-12, and Cognitive Control and Flexibility Questionnaire were applied to a sample of 3004 adults living in Turkey. The results of the analysis indicated that CF moderated the effect of IU on psychology symptoms. The slope analysis revealed a weakening association between IU and psychological symptoms with the introduction of a high CF level introduced to the model. The findings highlighted the importance of IU as a potential risk factor for developing psychological symptoms while CF appears as a potential protective factor during the COVID-19 pandemic.