This study assesses the determinants and severity of psychological distress among frontline Ministry of Health workers within Saudi Arabia during the rapid acceleration phase of the coronavirus disease 2019 (COVID-19) epidemic. Moreover, we assess distress sustainability and stress-coping behaviors. We conducted an online national cross-sectional survey. The Kessler Psychological Distress Scale (k10) is a highly reliable instrument used to assess depression and anxiety. We evaluated stress-coping behavior and the persistence of the disorders. Binary logistic regression identified the sociodemographic factors related to severe distress.The prevalence of severe psychological distress among COVID-19 frontline healthcare workers (HCWs) was 27.3%. Factors associated with severe psychological distress in multiple regression analyses were male gender (p < 0.001), working for >45 hours/week (p = 0.009), age of >40 years (p = 0.038), years of experience for more than seven years (p = 0.048), Asir region (p = 0.003), and using psychological services (p < 0.001). The prevalence of severe psychological distress was 27.3%. Factors associated with severe psychological distress in multiple regression analyses were male gender, working >45 hours/week, age, years of experience, region, and using psychological services. The results form a foundation for targeted psychological health support services at the individual and institutional levels to prevent progression to mental illness.