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This study aimed to examine the association between physical activity (PA), physical fitness, and health-related quality of life (HRQOL) among school-aged children. A prospective design was used in this study. Participants included 201 children (91 boys, 110 girls; Mean = 9.82 years) enrolled in a public school in the mid-South region. Results indicate both PA and physical fitness were positively associated with four functioning of HRQOL, including physical, psychosocial, emotional, and school functioning. Mediational analyses suggest that physical fitness emerged as a mediator between PA and HRQOL. Implications include PA and exercise intervention programs within or after school aiming at enhancing children’s physical fitness is highly recommended, which in return will have direct impact on their HRQOL.