Despite initiatives and management efforts to minimize exacerbation and adverse outcomes, asthma remains a leading cause of childhood chronic disease in the United States. Environmental, personal, and social factors have been associated with an increase of asthma morbidity. However, little is known about how they cumulatively affect children's quality of life. This study applied a multifactorial conceptual model grounded by the ecological systems theory framework to ascertain which environmental, personal, and social factors were cumulatively associated with adverse health-related quality of life (HRQoL) in children with asthma ages 5-17 years. A national, cross-sectional survey, the Behavioral Risk Factor Surveillance System Asthma Call-back Survey, of 2,968 (unweighted) participants were used to identify the association between the factors and HRQoL outcomes, symptom-free days, missed school, and activity limitations. Multiple linear regression and cumulative regression models for complex survey data were used to assess the associations. Factors associated with the HRQoL outcomes included cost barriers to asthma medications and primary care physicians, insurance status, having an insurance gap, the type of health insurance, the presence of mold in the school, the guardian's diminished mental health, and environmental tobacco smoke. Understanding which factors influence asthma HRQoL may foster positive social change by enlightening and empowering the child, caregivers, health care professionals, and other stakeholders to become active participants in the asthma management process. Therefore, quality of life is optimized by all participants taking an active role in the asthma management process through conversations and developing synergistic strategies.