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Estrogens are suggested to affect mood by binding to widespread estrogen receptors in the brain and therewith modulating a variety of neurosignaling pathways. Single nucleotide polymorphisms (SNPs) in the genes encoding estrogen receptors might influence these actions and thereby play a role in the genetic foundation of mood disorders. Several SNPs in the estrogen receptor 1 (ESR1) gene have been studied in relation to anxiety and depression, while confounders and interaction with psychosocial factors have largely been overlooked. The present study investigated the effect of the functional polymorphisms rs2234693 (PvuII) and rs9340799 (XbaI) in the ESR1 gene on depression and anxiety symptoms as well as their interaction with early life adversities and parenting in two independent female cohorts, considering relevant confounding factors. In adolescent females (n = 1036), the rs9340799 minor allele (G) was found to protect against increasing anxiety symptoms from age 14 to 17, whereas, in young adult females (n = 1314, mean age: 22.2 years), it was associated with a greater risk of experiencing above-threshold anxiety symptoms. No genetic effect was found for rs2234693 and depressive symptoms in either cohort. A significant three-way gene-environment interaction was observed between rs9340799, stressful early life events, and supportive parenting on anxiety symptoms in female adolescents. These findings suggest a potential differential plasticity of the G allele in relation to anxiety symptoms in female youth. By incorporating longitudinal assessments and gene-environment analyses, this study contributes to the literature on internalizing symptoms in females in the context of estrogen-related constitutive vulnerability.