Background: The COVID-19 pandemic has been around for more than a year as a global problem, with nurses being among the first groups involved in treating epidemics. In addition to becoming infected and dying from the disease, nurses also suffer from death anxiety, affecting their mental health. It is necessary to investigate the modulating factors of this anxiety. The purpose of this study was to predict mental health by religious orientation and the mediating role of death anxiety among nurses in the COVID-19 pandemic.Methods: The present descriptive-analytical and cross-sectional study was conducted on 208 nurses working in the Central Hospital for the Treatment of COVID-19 patients in the Persian Gulf Martyrs Hospital in Bushehr, who were enrolled in the census. Data collection tools were the General Health Questionnaire-28 (GHQ-28), the Templer’s Death Anxiety Scale (DAS), and the Revised Religious Orientation Scale (ROS). Data were analyzed by SPSS version 22 software using the Pearson correlation test and multiple regression analysis.Results: Among the subjects, 53.5% of nurses experienced high death anxiety. According to the findings, death anxiety had a significant negative effect on mental health (P<0.001, β=-0.54). Intrinsic religious orientation led to a reduction in death anxiety (P=0.01, β=-0.16) and improved mental health (P<0.001, β=0.40), while extrinsic socially-oriented religiousness resulted in increased death anxiety (P<0.001, β=0.19) and decreased mental health (P<0.001, β=-0.20).Conclusion: The prevalence of death anxiety in the COVID-19 pandemic was high in nurses, which led to a decrease in their mental health. The results of this study revealed that the intrinsic religious orientation had a positive effect on reducing death anxiety and promoting mental health.