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Background The current coronavirus disease (COVID-19) pandemic has had a great effect worldwide. Although health care workers (HCWs) play an essential role and are one of the most exposed groups, information about the psychosocial effect among the general population and those who came in contact with COVID-19-infected patients is still required. Aim The study's main aim was to assess the prevalence of anxiety and depression among the general population, those who came in contact with patients, and frontline HCWs in response to the COVID-19 pandemic in Egypt and to investigate factors associated with psychological distress. Materials and methods A cross-sectional study was carried out using an online-administered questionnaire. The questionnaire included sociodemographic data and data related to the current pandemic. Hospital-based anxiety and depression scale (HADS)-Arabic version was used to assess anxiety and depression. Multivariable logistic regression analysis was performed to identify significant predictors. Results A total of 1778 participants were involved in the current study, and of them, 82.6% were general population, 10.6% were HCWs, whereas those who came in contact with COVID-19-infected patients were 6.8%, with more female predominance. Of 1778 participants, 711 (40%) had abnormal depressive score. Overall, 52.9% of those who came in contact with COVID-19-infected patients had abnormal depressive score, whereas 39.4% and 36.5% of the general population and HCWs, respectively, had abnormal depressive score, with statistically significant difference. Regarding anxiety, there was a highly significant difference among the three groups with higher abnormal anxiety score among those who came in contact with COVID-19-infected patients (46.3%) than the general population and HCWs (33% and 33.9%, respectively). Overall, 34% of all participants had abnormal anxiety score. While evaluating different parameters associated with psychological distress by multiple logistic regression analysis, individuals without a history of previous psychological illness and those who rely on internet and approved sites as sources of information experienced less anxiety and depression. Female sex and lower levels of education have a higher risk of anxiety. Conclusions During the current pandemic, the Egyptian population has a high prevalence of psychological distress, with a higher prevalence among those who came in contact with COVID-19-infected patients than in the general population and HCWs. Among different parameters associated with psychological distress, individuals without a history of previous psychological illness and those who rely on internet and approved sites as sources of information experienced less anxiety and depression during the COVID-19 pandemic. Therefore, establishing early targeted mental health interventions should become routine as a part of our preparedness efforts. [ABSTRACT FROM AUTHOR]