Purpose: This study was aimed to analyze the mediation role of cardiorespiratory fitness (CRF) on the association between fatness and cardiometabolic risk scores (CMRs) in European adolescents. Methods: A cross-sectional study was conducted in adolescents (n = 525; 46% boys; 14.1 ± 1.1 years old, mean ± SD) from 10 European cities involved in the Healthy Lifestyle in Europe by Nutrition in Adolescence study. CRF was measured by means of the shuttle run test, while fatness measures included body mass index (BMI), waist to height ratio, and fat mass index estimated from skinfold thicknesses. A clustered CMRs was computed by summing the standardized values of homeostasis model assessment, systolic blood pressure, triglycerides, total cholesterol/high-density lipoprotein cholesterol ratio, and leptin. Results: Linear regression models indicated that CRF acted as an important and partial mediator in the association between fatness and CMRs in 12–17-year-old adolescents (for BMI: coefficients of the indirect role β = 0.058 (95% confidence interval (95%CI): 0.023–0.101), Sobel test z = 3.11 (10.0% mediation); for waist to height ratio: β = 4.279 (95%CI: 2.242–7.059), z =3.86 (11.5% mediation); and for fat mass index: β = 0.060 (95%CI: 0.020–0.106), z = 2.85 (9.4% mediation); all p < 0.01). Conclusion: In adolescents, the association between fatness and CMRs could be partially decreased with improvements to fitness levels; therefore, CRF contribution both in the clinical field and public health could be important to consider and promote in adolescents independently of their fatness levels.