Purpose: This study was to investigate the mediating effects of health concern and depression on the stress and fatigue of COVID-19 self-quarantine. Methods: This was a cross-sectional study. A total of 227 people with COVID-19 self-quarantine experience were recruited during May 2021. Participants were invited to complete self-reported questionnaires that measure stress, health concern, depression, fatigue and demographic information. The data obtained were analyzed using multiple regression and dual mediation model applying the PROCESS macro with 95% bias-corrected bootstrap confidence interval. Results: This study analyzed the direct effects of COVID-19 stress on the health concern, depression and fatigue. And COVID-19 stress had indirect effects on their fatigue via health concern and depression. Both health concern and depression had dual mediating effects in the influence of COVID-19 stress on fatigue. In the relationship between COVID-19 stress and fatigue, the mediating effect of depression was significant. Conclusion: Fatigue due to prolonged COVID-19 can be alleviated by managing stress and mediating health concern and depression, and so therefore active nursing intervention is required.