Abstract Background Adolescents having early puberty (EP) are more likely to have obesity and increased cardiometabolic and inflammatory markers and atherosclerosis risk. We aimed to assess the indirect and mediated effects of leptin and adiposity on the relation between EP and cardiometabolic and inflammatory markers in European adolescents. Methods A sample of 511 adolescents with EP (12.5–17.5 years) from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study was studied. To assess whether leptin levels and adiposity mediate the relation between EP and several biomarkers, linear regression models for mediation analyses were performed. Results EP was positively associated with the atherogenic index (Ath-I) (β=0.174; 95%CI 0.029–0.265) and negatively associated with the C-reactive protein (CRP) (β=−0.284; 95%CI −0.542 to −0.028) in girls. These associations were fully mediated by leptin levels (9.5%) and adiposity (44%), respectively. Moreover, EP has indirect effects on the apolipoprotein A-1 (ApoA-1) levels through adiposity in girls (for body mass index [BMI], β=0.014; 95%CI 0.005–0.028, and for waist circumference [WC], β=0.011; 95%CI 0.003–0.024), and on ApoA-1 (β=0.012; 95%CI 0.004–0.025), apolipoprotein B (ApoB) (β=−0.004; 95%CI −0.011 to −0.0004) and CRP (β=−0.265; 95%CI −0.819 to −0.047) through abdominal fat in boys. Conclusions Leptin levels and adiposity seem to play an important indirect and mediation role in the association between EP and cardiometabolic and inflammatory markers in adolescents. Weight control should be recommended in order to control the impaired cardiometabolic and inflammatory status arising in early pubertal adolescents.