Background: The COVID-19 pandemic intensely involved pharmacists in France, with new responsibilities on a large scale, introducing to dispensary practice the performance of vaccination and nasopharyngeal swabs. This study aimed to assess the prevalence of burnout, anxiety, and depression in pharmacists after the COVID-19 health crisis and to identify factors associated with psychological distress. Methods: A cross-sectional observational study involved 1700 pharmacies in an entire French region. Sociodemographic, geographical, and medical information (burnout tested with the MBI and anxiety/depression measured on the HAD scale) were collected via an online anonymous self-administered questionnaire. The characteristics of the pharmacy and the practice of antigen testing and vaccination were requested. Quantitative and qualitative variables associated with psychological distress were investigated with a factor analysis. Results: In total, 360 responses were collected (20.5%). Of the responses, 41.9% showed definite anxiety symptoms and 18.3% showed proven depressive symptoms. Three clusters were described according to the intensity of burnout experience, depersonalization, and loss of personal accomplishment. The analysis identified that one cluster was at high risk of burnout (high burnout and depersonalization scores). Of these stressed, exhausted pharmacists, 69.3% showed definite anxiety, 37.9% showed proven depression, and in smaller pharmacies. The carrying out of antigenic testing and anti-COVID vaccination, as well as the geographical location of the pharmacy, were not discriminating factors in these three groups. Conclusion: Mental health care and suicide prevention should be provided to at-risk pharmacists. It seems essential to publicize the range of resources available to support pharmacists.