Purpose: We investigated the combined effect of cardiorespiratory fitness and the clustered score of inflammatory biomarkers (InflaScore) on the cardiometabolic risk score in adolescents. Methods: This is a cross-sectional analysis with 529 adolescents (267 girls) aged 12–18 years. The shuttle run test was used to assess cardiorespiratory fitness. Continuous scores of clustered inflammatory biomarkers (high sensitivity C-reactive protein, complement factors C3 and C4, fibrinogen and leptin); cardiometabolic risk score (systolic blood pressure, triglycerides, ratio total cholesterol/HDL, HOMA-IR and waist circumference) were computed. Results: Adolescents with a higher inflammatory profile had the highest cardiometabolic risk score; adolescents with high InflaScore and low fitness had the highest odds of having a high cardiometabolic risk (OR 16.5; 95% CI 7.8–34.5), followed by adolescents with a higher InflaScore but fit (OR 7.5; 95% CI 3.7–8.4), and then by adolescents with a low InflaScore and unfit (OR 3.7; 95% CI 1.6–8.4) when compared to those with low InflaScore and fit, after adjustments for age, sex, pubertal stage, adherence to a Mediterranean dietary pattern and socioeconomic status. Conclusions: The findings of our study suggest that the combination of high inflammatory state and low cardiorespiratory fitness is synergistically associated with a significantly higher cardiometabolic risk score and thus supports the relevance of early targeted interventions to promote physical activity and preservation as part of primordial prevention.