Background: Breast cancer may impair health-related quality of life (HRQoL). We examined the mediating roles of perceived social support (PSS) and coping style (CS) in the relationship between resilience and HRQoL in newly diagnosed breast cancer patients. Methods: Four-hundred thirty-one patients completed a survey at two hospitals in Shaanxi Province, China using self-report measures assessing HRQoL, resilience, PSS, and CS. A one-sample t-test analyzed differences between resilience, PSS, and CS in breast cancer patients and the corresponding norm. Multivariate linear regression analyzed the independent predictors of HRQoL. The mediating roles of PSS and CS between resilience and HRQoL were investigated using structural equation modeling (SEM). Results: Participants had significantly lower scores for resilience and PSS, and higher scores for the avoidance and resignation CSs than their corresponding norm. SEM analysis showed resilience had significant direct effects on PSS (B = 0.59, 95% CI [0.49, 0.68], P = 0.003), CS (confrontation: B = 0.53, 95% CI [0.44, 0.62], P = 0.001; resignation: B = -0.66, 95% CI [-0.74, -0.57], P = 0.002), and HRQoL (B range from 0.54–0.58). Resilience had significant indirect effects (B range from 0.09–0.27), and PSS and CS had significant direct effects on HRQoL (P < 0.05). Conclusions: Newly diagnosed breast cancer patients had lower resilience and PSS, and higher negative CSs. PSS and CS appeared to mediated the influence of resilience on HRQoL. Multimodal intervention programs focusing on PSS and CS might increase the influence of resilience on HRQoL in breast cancer patients.