In early 2023, China experienced its first widespread COVID-19 outbreak after a policy shift. This study examines the relationship between fatigue and COVID-19-related post-traumatic stress symptoms (PTSS) in infected and uninfected individuals, exploring the potential mediating role of insomnia symptoms. An online survey of 5953 Chinese participants was conducted from 10 to 16 January 2023. Participants reported their COVID-19 infection status, fatigue, insomnia symptoms, and PTSS. Multi-group structural equation modeling (SEM) was used to test whether the mediation paths differed between infected and uninfected groups. The prevalence of fatigue, insomnia symptoms, and COVID-19 PTSS were 30.0%, 36.4%, and 5.8%. The SEM based on the bootstrapping showed that after controlling for demographics, chronic fatigue positively associated with COVID-19 PTSS in a significant way, with insomnia symptoms playing a mediating role. The multi-group analyses further revealed a partial mediation effect of insomnia symptoms on the relationship between fatigue and COVID-19 PTSS in the uninfected group (UG). However, for the infected group (IG), insomnia symptoms fully mediated the relationship between fatigue and COVID-19 PTSS. Infected individuals were more subject to the aforementioned mechanism than uninfected individuals. Addressing chronic fatigue, insomnia, and developing targeted interventions are crucial for supporting mental health across different infection statuses.