Background: The uncontrolled spread of the COVID-19 disease in India's second wave post-February 2021, put to task the public health system across the nation. This, in turn, exhausted our health-care workforce both physically and mentally. To establish the prevalence of psychological symptoms and guide the action plan in place, the present study was undertaken among COVID-19 health-care workers (HCWs) at tertiary-care public hospital, Mumbai. Materials and Methods The present cross-sectional study was conducted after due institutional ethical clearance among 212 HCWs engaged in the management of COVID-19 patients during the second wave. A Google Form® was created in English, Hindi, and Marathi languages for self-administration. Data were collected under three domains; informed consent, sociodemographic and workplace-related details, and DASS-21 Questionnaire scores. This was further subjected to statistical analysis using SPSS® software. Results This study included 90 (42.5%) doctors, 91 (42.9%) nurses, and 31 (14.6%) other categories of HCWs. Depression was prevalent in 44.3% HCWs, while 43.9% and 36.3% of the HCWs were affected by anxiety and stress, respectively. Younger population, female gender, and doctors were associated (P < 0.05) with an increased likelihood of either of the prevalent psychological symptoms. Other significantly associated (P < 0.05) factors included COVID-19 vaccination status of the HCW, history of COVID-19 infection, infected colleague at workplace, workplace housing facilities and commute, number of dependents on the HCW and hospitalized family member or close friend. Conclusion The COVID-19 HCWs were found to be under considerable psychological strain. In essence, screening, identifying, and effectively targeting HCWs for psychological interventions is needed to protect and strengthen the health-care system.

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