The COVID-19 pandemic has led to hardship for individuals across the globe, and research to-date has indicated a significant impact of the pandemic on mental health functioning. In order to promote psychological resilience during this time, it is important to understand modifiable targets for clinical intervention. The current study examined demographic characteristics, pandemic-related adversity, and psychological flexibility in relation to general and peritraumatic distress in a sample of United States survey respondents during May of 2020. Participants were recruited from Amazon Mechanical Turk (MTurk),  = 485. Participants completed measures of pandemic-related adversity, psychological flexibility components (openness to experience, behavioral awareness, and valued action), peritraumatic distress, and general distress. Hierarchical regression analyses examined whether demographic characteristics, pandemic-related adversity, and components of psychological flexibility were associated with general and peritraumatic distress. Results indicated that higher pandemic-related adversity, lower openness to experience, and lower behavioral awareness were significantly associated with higher general distress. Greater pandemic-related adversity, lower openness to experience, lower behavioral awareness, and higher valued action were significantly associated with higher peritraumatic distress. Adding the components of psychological flexibility to the model increased the amount of variance accounted for in both measures of distress. The results indicated that psychological flexibility components may be particularly important targets for prevention and intervention efforts in the midst of the COVID-19 pandemic. Transdiagnostic interventions, such as Acceptance and Commitment Therapy, that target psychological flexibility may be useful as the impact of the pandemic continues to unfold.