BACKGROUND: Nurses worldwide were exposed to increased levels of occupational stress during the COVID-19 pandemic which could have hindered their level of health-related quality of life (HRQoL). OBJECTIVES: This project investigated HRQoL level in nurses during the COVID-19 pandemic and its health and occupational predictors. METHODS: A cross-sectional design was adopted and targeted full-time nurses in Jordan. Study collected data included demographics, 12-item Short Form health survey (SF-12) to measure HRQoL, Nordic musculoskeletal questionnaire (NMQ), nurses’ evaluation of work conditions during COVID-19, and Depression Anxiety Stress Scale (DASS21). Data was analyzed descriptively to summarize main outcome measures and using multiple linear regression model to identify factors significantly associated with HRQoL. RESULTS: In total 245 nurses successfully completed the survey, 39.6% were males with a mean age of 35±6 years. Participant SF12 scores were 65.94±17.85 for physical component and 50.09±19.36 mental component. The statistical model significantly explained 53.2% of variance in HRQoL (r2 = 0.534, F = 57.849, p < 0.001). Better sleep quality self-evaluation was significantly associated with higher HRQoL levels, while increased levels of depression, musculoskeletal pain, and financial burden on family were significantly associated with worse HRQoL level. CONCLUSION: Jordanian nurses’ HRQoL level was relatively low during COVID-19. Sleep quality, mental health status, musculoskeletal health status, and financial status were identified as factors possibly influenced HRQoL among nurses during the COVID-19 pandemic. Nurses’ quality of life along with their mental and physical health should be considered by healthcare administrators in the remaining period of COVID-19 and in future similar emergencies.