Background: COVID-19 was declared as a pandemic by the World Health Organization (WHO) in March 2020. It has affected millions globally and remains as a public health concern until today. Objectives: The study aims to identify the prevalence of depression, anxiety and stress among UST hospital frontliners during the COVID-19 pandemic using the Depression, Anxiety and Stress Scale (DASS)-21 scale. Methods: A cross-sectional study was conducted among 272 frontliners in a tertiary hospital in Manila, Philippines using the DASS-21 scale. Results: Based on data gathered from the responses of participants using the DASS-21 scale, the prevalence of depression, anxiety and stress among the frontliners were 28.68%, 35.66% and 14.71%, respectively. Being single, living alone, higher degree of educational attainment (postgraduate), trainees (residents and fellows) and those having pulmonary comorbidities were associated with increasing level of depression and stress. Respondents who had less work experience (less than 5 years) had significant depression; being single presented with higher anxiety; and those who had a previous COVID-19 infection had higher degree of stress. Conclusion: Several demographic and occupational characteristics, in accordance to the COVID-19 pandemic, yielded significant results regarding the presence of depression, anxiety and stress. The study recommends closer follow-up of participants which recorded high severity scores in the DASS-21 scale as well as regular psychological briefing and counseling to assess if there are other contributory factors to such responses. Ultimately, this may enlighten us on how to provide holistic care to our own hospital staff. Keywords: COVID-19, Depression, Anxiety, Stress, DASS-21 scale