Objective: The HEPAKID index, a novel diagnostic tool with a sensitivity of 82% and specificity of 62% for detecting nonalcoholic fatty liver disease in obese adolescents. Our study aimed to explore the potential relationship between the HEPAKID index and risk factors contributing to the development of cardiovascular disease in obese adolescents with metabolic syndrome. Methods: This prospective cross-sectional study, conducted at two medical centers from December 2023 to March 2024, included 208 obese adolescents, with a median age of 14.5 years and an average body mass index (BMI) of 30.57 kg/m2. Results: Elevated HEPAKID index values were found in obese adolescents with metabolic syndrome, showing positive associations with BMI, waist and hip circumferences, alanine aminotransferase level, fasting insulin, and homeostasis model assessment for insulin resistance. In those with metabolic syndrome, waist circumference (WC) and homeostasis model assessment for insulin resistance were significant independent variables linked to the HEPAKID index, while WC was the sole influencer in the nonmetabolic syndrome group. Multivariate logistic regression highlighted systolic and diastolic blood pressures, triglycerides, high-density lipoprotein cholesterol, and the HEPAKID index as reliable predictors of metabolic syndrome. A predictive cutoff value of 60.84 for the HEPAKID index showed 61.7% sensitivity and 59.1% specificity in identifying metabolic syndrome. Conclusions: Our study highlighted the potential value of the HEPAKID index in combination with other clinical parameters for predicting metabolic syndrome in obese adolescents, underscoring its role as a valuable screening tool. Furthermore, our findings revealed a correlation between the HEPAKID index and insulin sensitivity in this high-risk population.