BACKGROUND: The sudden shift into distance learning during the coronavirus (COVID-19) lockdown might have impacted university students’ well-being. OBJECTIVE: This study aimed to investigate undergraduate healthcare university students’ health-related quality of life (HRQoL) and its predictors during COVID-19. METHODS: A cross-sectional study used an online self-administered questionnaire. The study targeted undergraduate medical, dental, pharmacy, and nursing students at Jordanian universities. Data collected included demographics,12-item Short Form health survey (SF-12), students’ evaluation of distance learning, Neck Disability Index (NDI), Depression Anxiety Stress Scale (DASS21), and the International Physical Activity Questionnaire (IPAQ). Descriptive analyses were conducted to summarize primary outcome measures data. Predictors of HRQoL were determined using a multiple variable regression analysis. RESULTS: In total, 485 university students successfully completed this study with a mean age of 20.6 (±2.0). Participants’ HRQoL level measured by SF-12 mean scores were 66.5 (±20.2) for physical health component and 44.8 (±21.2) for mental health component. The regression model explained 65.5% of the variation (r2 = 0.655, F = 127.8, P < 0.001) in participants’ HRQoL. Factors significantly associated with HRQoL included depression, neck disability index score, stress, health self-evaluation, average of satisfaction with distance learning, IPAQ score, and weekly studying hours. CONCLUSIONS: This study showed that healthcare students had a relatively low level of HRQoL during COVID-19 pandemic in Jordan. Academic and non-academic factors associated with HRQoL were identified and should be considered by healthcare educational institutions for better academic planning in future similar pandemics.