The COVID-19 pandemic has resulted in much psychological distress amongst healthcare workers, primarily those serving in COVID-19 hospitals. This can lead to high levels of burnout, as healthcare workers experience increasingly challenging working environments. However, it is crucial to examine the factors underlying depression and anxiety, specifically the psychological and non-psychological variables. Additionally, the new constructs of stress of COVID-19 have emerged, suggesting that the stressors of this pandemic are very divergent from previously. A cross-sectional study was performed amongst 210 healthcare workers in a tertiary non-COVID hospital in Kota Kinabalu, Sabah, Malaysia. Questionnaires corresponding to the following variables were administered: non-psychological variables (operationalized as age, gender and living status); psychological variables (operationalized as burnout, psychological inflexibility, state mindfulness, and stress of COVID-19); and psychological distress (depression, anxiety, and stress). Bivariate correlations were assessed amongst all continuous variables. Subsequently, stepwise regression analysis was performed using depression and anxiety as separate dependent variables. Psychological inflexibility, stress of COVID-19, and dysfunctional coping styles emerged as predictors for both depression and anxiety. Work-related burnout emerged as an additional predictor for depression but not anxiety. This study demonstrates significant theoretical contribution and clinical implications in healthcare practice by addressing the impact of various COVID-19 related psychological and non-psychological variables on healthcare workers in non-COVID tertiary hospitals. This study will help healthcare workers to understand the relevant skills in mitigating depression and anxiety during pandemic.