Problematic gaming has become a public concern, influenced both by genetic factors and stressful environments. Studies have reported the effects of dopamine-related genes and interpersonal stressors on problematic gaming, but gene and environment interaction (G × E) studies have not been conducted. In this study, we investigated the interaction effects of dopamine receptor D2 (DRD2) polymorphisms and interpersonal stress on problematic gaming and the mediating effect of avoidant coping to reveal the mechanism of the G × E process. We recruited 168 college students (mean age = 22; male 63.1%) and genotyped their DRD2 C957T (rs6277) and Taq1 (rs1800497) polymorphisms. The results of the mediated moderation analysis showed that, when experiencing interpersonal stressors, individuals with both the C957T T allele and the Taq1 A1 allele showed more elevated problematic gaming scores than non-carriers. Moreover, the interaction effect of the combined DRD2 polymorphisms and interpersonal stress was significantly mediated by avoidant coping. These findings suggest that the influence of interpersonal stress on problematic gaming can be changed as a function of DRD2 genotypes, which may be because of the avoidant coping styles of C957T T allele and Taq1 A1 allele carriers in response to stress.