Aim: A nested case–control study was conducted to establish an association of placental tissue estrogen receptor alpha gene expression with postpartum depression. Materials and methods: Antenatal women were enrolled in their third trimester, and after delivery, their placentas of 1 × 1 cm were stored in freezer at −80°C. Women were evaluated at 2 weeks and 6 weeks after delivery by Edinburgh Postnatal Depression Scale (EPDS) Hindi version, to identify postpartum depression (PPD) cases and controls. Results: Out of 209 eligible women recruited, 30 PPD cases and 30 controls were identified on follow-up visits, and then, their stored placental tissues were analyzed for ESRα gene expression and the quantitative levels of ESRα RNA expression were evaluated. It was observed that ESRα gene was significantly downregulated by 1.33 times among cases as compared to controls, and the placental ESRα delta Ct value among cases was significantly higher with respect to controls. Conclusion: Women developing PPD after delivery have significantly lower expression of ESRα gene in their placenta at the time of delivery, which is 1.33 times less as compared to women who remain healthy. The mean ESRα delta Ct value in PPD cases (3.33 ± 0.697 SD) was significantly higher than the controls (2.91 ± 0.759 SD), with p value 0.032. Thus, the downregulation of placental ESRα gene expression at delivery plays a crucial role in PPD.