On-site experiences and reports have shown that the multiple outbreaks of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC) resulted in pervasive experience of stigma against many people who have recovered from EVD as well as their families and close relatives. Three evidence-based protective factors which are supposed to mitigate the impact of enacted Ebola stigma on health-related quality of life (HRQoL) of individuals in this epidemic context were identified. We expected that positive religious coping, perceived social support, and general self-efficacy would mediate the relationship between enacted Ebola stigma and HRQoL. These hypotheses were tested through multiple mediation model using the structural equation modeling among a large sample of adult populations (N = 1614; 50% women) in the province of Equateur in the DRC, in the aftermath of the 9th Ebola outbreak. The mediation model yielded adequate fit statistics and the results provided strong evidence that higher levels of enacted Ebola stigma were associated with lower HRQoL. They confirmed the synergetic mediating effects of positive religious coping, perceived social support from family (but not from others sources) and general self-efficacy. Futher exploratory findings revealed that the perceived social support from family buffered the impact of enacted Ebola stigma on HRQoL. If replicated by a longitudinal study, our findings lay a solid foundation for empirical-based community mental health interventions for reducing enacted Ebola stigma and promoting HRQoL during epidemics, especially in the DRC.