To verify the role of the combination of fitness and fatness in the relationship between physical activity (PA) and cardiometabolic risk in children and adolescents. This is a cross-sectional study performed with 2786 children and adolescents (6 to 17 years). Fitness was determined by the cardiorespiratory fitness (CRF) six-minute walking and running test. Waist circumference (WC) was considered a fatness indicator. A self-reported questionnaire was used to determine PA practice, whereas the clustered cardiometabolic risk score (cMetS) wascalculated by summing z-scores of triglycerides, totalcholesterol/HDL-C ratio,systolic blood pressure, glucose, and WC. Considering the combination of CRF (fitness) and WC (fatness), the following phenotypes were created: Fit/Unfat, Fit/Fat, Unfit/Unfat and Unfit/Fat. Moderation analyses were tested using linear regression models. Significant interactions were found between PA and Unfit/Fat category (β = -0.001; p = 0.001) only for adolescents. The interaction observed in the Unfit/Fat phenotype indicated that adolescents who practise PA for 330 minutes per week presented lower cMetS compared to those who do not practise or practise for 60 minutes respectively. The combination of fitness and fatness moderates the relationship between PA and cardiometabolic risk, suggesting that adolescents, particularly those who are less fit and present high adiposity, should be encouraged to engage in regular PA to improve their metabolic health.