Objective <p>Creativity drives both individual progress and societal development. With the development of the gene-environment interaction theory, investigating the physiological and psychological mechanisms underlying creativity has become increasingly essential. Grounded in Bronfenbrenner’s ecological systems theory, this study employs the gene-environment (G × E) paradigm to investigate the interaction between serotonin system genes and the parent–child relationship in influencing adolescent creativity.</p> Methods <p>In study 1, questionnaire surveys and DNA genotyping techniques were used to select a sample of 707 middle school students (Mage = 13.95, SD = 0.42). The 5-HT MGPS was constructed by including TPH2 rs4570625, SLC6A4 rs1042173, 5-HTR1A rs6295, and MAOA rs6323 genes to examine the interaction between the parent–child relationship and 5-HT MGPS in influencing adolescent creativity. In study 2, a behavioral experiment on creativity was conducted as supplementary data to further validate the robustness of the interaction between the parent–child relationship and 5-HT MGPS in predicting creativity.</p> Results <p>(1) Parent–child relationship positively predicts adolescent creativity; (2) Data from both questionnaires and behavioral experiments indicate that the interaction between parent–child relationship and 5-HT MGPS predicts creativity; (3) The results of regions of significance test support the hypothesis that the interaction pattern between parent–child relationship and 5-HT MGPS aligns with the differential susceptibility model.</p> Conclusions <p>These findings highlight the critical role of the interaction between genetic and environments on creativity. Furthermore, the interaction pattern between the parent–child relationship and 5-HT MGPS aligns with the differential susceptibility model, suggesting that the environment can moderate the influence of genetic factors to a certain extent.</p>