Context: Childhood cancer survivors experience chronic health conditions that impact health related quality of life (HRQOL) and participation in optimal physical activity. Objective: The study aimed to determine independent effects of endocrine and metabolic disorders on HRQOL and physical activity. Design, Setting, and Patients: Retrospective cohort with longitudinal follow-up of survivors of childhood cancer enrolled in the North American Childhood Cancer Survivor Study. Main Outcome Measures: Medical Outcomes Short Form-36 estimated HRQOL while participation in physical activity was dichotomized as meeting or not meeting recommendations from the Center for Disease Control and Prevention. Log binomial regression evaluated the association of each endocrine/metabolic disorder with HRQOL scales and physical activity. Results: Of 7,287 survivors, median age 32 years (18-54) at their last follow-up survey, 4,884 (67%) reported one or more endocrine/metabolic disorders. Survivors with either disorder were significantly more likely to be male, older, received radiation treatment, and experience other chronic health conditions. After controlling for covariates, survivors with any endocrine/metabolic disorder were more likely to report poor physical function risk ratio ([RR] 1.25; 95% confidence interval [CI] 1.05-1.48), increased bodily pain (RR 1.27; CI 1.12-1.44), poor general health (RR 1.49; CI 1.32-1.68) and lower vitality (RR 1.21; CI 1.09-1.34) compared to survivors without. The likelihood of meeting recommended physical activity was lower among survivors with growth disorders (RR 0.90; CI=0.83-0.97), osteoporosis (RR 0.87; CI=0.76-0.99), and overweight/obesity (RR 0.92; CI 0.88-0.96). Conclusion: Endocrine and metabolic disorders are independently associated with poor HRQOL and sub-optimal physical activity among childhood cancer survivors.