We examined whether physical activity (PA) influences the association between birth weight and serum leptin in adolescents. The study comprised a total of 538 adolescents (315 girls), aged 12.5–17.49 years, born at term (≥37 weeks of gestation). We measured serum leptin levels and time engaged in moderate-vigorous PA (MVPA) by accelerometry. There was an interaction effect between birth weight and meeting the PA recommendations (60 min/day MVPA) on leptin levels in girls (P = 0.023) but not in boys (P = 0.809). Birth weight was negatively associated with leptin levels in girls not meeting the PA recommendations (i.e. more than 60 min/day of MVPA) (β = −0.096, P = 0.009), whereas no significant association was observed in those meeting the PA recommendations (β = −0.061, P = 0.433). In conclusion, meeting the PA recommendations may attenuate the negative effect of low birth weight on serum leptin levels in European female adolescents.