To test the hypothesis that resilience has a mediating effect on the association between work fatigue and psychological distress. A cross-sectional survey was conducted online in eight countries in 2021: Brazil, Lebanon, Nigeria, Pakistan, Poland, Qatar, Serbia, and Tunisia. A total of 1094 healthcare professionals specialized in medicine, pharmacy, and nurse practitioners that were exposed to/worked with COVID-19 patients were included (age: 33.89 ± 10.79 years; 59.6% females). After adjusting for potential confounders (i.e., country, gender, primary work in emergency department, primary work in infectious disease, primary work in intensive care unit, working in a COVID-19 ward, and working voluntary hours), the results of the mediation analysis showed that resilience fully mediated the association between physical work fatigue and psychological distress and partially mediated the associations between mental and emotional work fatigue and psychological distress. Higher work fatigue was significantly associated with less resilience; higher resilience was significantly associated with less psychological distress. Finally, higher mental and emotional, but not physical, work fatigue, were directly and significantly associated with more psychological distress. Identifying resilience as an important mediator in the path from fatigue to distress helps elucidate underlying mechanisms and pathways leading to the mental health-alteration process among healthcare workers during COVID-19. New strategies targeting resilience may be developed to further improve mental health outcomes among healthcare workers.