Depression is a widespread emotional disorder and mental health problem worldwide, and it is also one of the main causes of the burden of disease and disability. Early adolescence is a critical period for depression onset. According to ecological system theory, parenting as an important family factor, is significantly associated with depression. However, it is well-known that not all individuals who have experienced high levels of negative parenting or low levels of positive parenting would suffer from depression. Behavioral genetics studies have shown that COMT gene, 5-HTR1A gene and BDNF gene are important candidate genes for depression. Negative life events have also been indicated to play a key role in depression development. Additionally, developmental contextualism holds that an individual’s development is affected by the interaction of different situations in which it is located. However, it is unclear whether negative life events can co-moderate parenting with polygenes on early adolescent depression. Furthermore, extensive studies have demonstrated that there are gender differences in the interaction of genes and environment on depression. Therefore, the present study aimed to investigate the moderating role of cumulative genes score (CGS) and negative life events on the association between parenting and early adolescent depression, and its possible gender difference. Participants were 745 adolescents (Mage = 13.36 years, male = 53.29%) from Grades 7 to 9. The adolescent depression, parenting and negative life events were assessed using Center for Epidemiologic Studies Depression Scales (CES-D), parenting questionnaire and adolescent life events scale, respectively. All measures showed good reliability. DNA was extracted from saliva. Genotypes at Val158Met polymorphism, C-1019G polymorphism and Val66Met polymorphism were performed for each participant with MassARRAY RT software version 3.0.0.4 and analyzed using the MassARRAY Typer software version 3.4 (Sequenom). A series of hierarchical regressions were conducted to test the three-way interactions among cumulative gene scores of three polymorphisms, parenting and negative life events on depressive symptoms, separately for male and female adolescents. The Benjamini-Hochberg program (1995) was used to correct the significance of the regression analysis results to reduce the incidence of type I errors. The results revealed that there was a significant association between parenting and depression. That is, adolescents exhibited more depression when exposed to higher negative parenting or lower positive parenting. Besides, the cumulative gene scores and negative life events could significantly moderate the effect of paternal positive parenting on adolescent depression, but this moderating effect only existed in male adolescents. Specifically, among male adolescents who experienced more negative life events and carried more plasticity alleles, the paternal positive parenting could negatively predict adolescent depression, whereas such association was not observed among their counterparts. Additionally, the findings indicated that both negative parenting and maternal positive parenting had no significant interactions with cumulative gene scores and negative life events. In summary, the results of our investigation indicated that polygenes and negative life events could moderate the effect of parenting on early adolescent depression, and there was a gender difference in the moderating effect. Our findings highlight the importance of considering multiple genes and multiple environments when examining the underlying mechanism of early adolescent depression, and also provide important implications for the personalized intervention of adolescent depression.