Genetic variants that regulate hypothalamic–pituitary–adrenal (HPA) axis function have been demonstrated to moderate the association between parenting and mental health. However, extant research has focused primarily on (i) effects of individual genes or (ii) maternal as opposed to paternal parenting. Using a multilocus genetic profile score (MGPS) approach, the current study is the first to examine the moderation effect of multilocus HPA-axis related genetic variants on the association of both maternal and paternal parenting with adolescent internalizing and externalizing symptoms. In a sample of 772 Chinese Han adolescents (M age = 16.48 ± 1.40 years; 50.1% girls), a theory-driven MGPS was calculated using six polymorphisms within HPA-axis related genes (CRHR1, NR3C1, NR3C2, FKBP5, COMT, and HT1RA). Results showed that the MGPS interacted with both maternal and paternal parenting in the association with adolescent internalizing symptoms, but not externalizing symptoms. Consistent with the differential susceptibility model, adolescents with high versus low MGPS exhibited not only more internalizing symptoms when exposed to low quality of parenting but also less internalizing symptoms when exposed to high quality of parenting. The current findings highlight the potential value of using a multilocus approach to understanding gene-by-environment interaction (G×E) effects underlying mental health. Within such G×E effects, not only maternal but also paternal parenting should be addressed.