OBJECTIVE The objective was to investigate the serial mediating effects of daily activities, patient health communication, and disease-specific worry in the relationship between pain intensity and overall generic health-related quality of life (HRQOL) in pediatric patients with Duchenne muscular dystrophy from the patient perspective. METHODS Pain Intensity Item, Daily Activities Scale, Communication Scale and Worry Scale from Pediatric Quality of Life Inventory (PedsQL) Duchenne Muscular Dystrophy Module and PedsQL 4.0 Generic Core Scales were completed by 110 pediatric patients with Duchenne muscular dystrophy ages 8-17. A serial multiple mediator model analysis was conducted to test the hypothesized sequential mediating effects of daily activities, patient health communication, disease-specific worry as intervening variables in the association between the pain intensity predictor variable and overall generic HRQOL. RESULTS Pain predictive effects on overall generic HRQOL were serially mediated by daily activities, patient health communication, and disease-specific worry. In a predictive analytics model utilizing hierarchical multiple regression analysis with age demographic covariate, patient-reported pain intensity, daily activities, patient health communication, and disease-specific worry accounted for 47% of the variance in overall generic HRQOL (P < 0.001), representing a large effect size. CONCLUSIONS Pain intensity, daily activities, patient health communication, and disease-specific worry explain in part the mechanism of pain predictive effects on overall generic HRQOL in pediatric patients with Duchenne muscular dystrophy. Identifying the mediators of pain intensity on overall generic HRQOL from the patient perspective may inform targeted clinical interventions and future patient-centered clinical research to improve overall daily functioning.