Introduction <p>To evaluate whether BMI status influences POMC methylation levels and subsequently affects the course of adolescent depression. This study examined the relationship between the methylation levels of different CpG sites in the POMC gene and clinical symptoms across various BMI categories in adolescent depression.</p> Methods <p>A total of 108 adolescent patients with depressive disorders including 68 with unipolar depression and 40 with bipolar depression participated in the study. They were divided into three groups: 11 underweight individuals (BMI below the age-specific threshold), 75 normal-weight individuals (BMI within the defined normal range), and 22 overweight individuals (BMI between the overweight threshold and obesity threshold). Pyrosequencing methylation analysis was used to assess POMC gene promoter methylation levels</p> Results <p>Adolescents in the overweight group exhibited significantly lower methylation levels at CpG6 and CpG8 of the POMC gene compared to their normal-weight and underweight peers. Furthermore, methylation at these sites was associated with clinical and psychological indicators such as Childhood Trauma Questionnaire (CTQ) and Montgomery–Asberg Depression Rating Scale (MADRS) scores. After adjusted for medication use, multivariate linear regression analysis revealed a negative correlation between CpG6 methylation levels and CTQ scores in overweight group.</p> Conclusion <p>This study shows the association between POMC methylation levels and depressive symptoms in adolescents across different BMI categories. The findings suggest a potential interaction between epigenetic mechanisms, depression and overweight providing a foundation for further mechanistic investigations.</p> Trial registration <p>Not applicable.</p>