Background Neonatal intensive care unit (NICU) hospitalization of newborn babies has been shown to have a negative impact on the mental health of postpartum women. The mental health of new mothers may be further burdened by the effects of the coronavirus disease 2019 (COVID-19) pandemic on social, economic, and psychological dimensions. This study aimed to evaluate postpartum depression and related factors in mothers of infants hospitalized in NICU during two distinct COVID-19 pandemic periods and examine anyadditional effects of the pandemic on the mental health of postpartum women. Methodology The Edinburgh Postpartum Depression Scale (EPDS) was applied to 250 NICU mothers during the COVID-19 pandemic. The first 125 women's children were hospitalized during a period of high number of cases and deaths when restrictions were in place for NICU parental visits (November 2021 to February 2022, the early group). The remaining 125 women completed the scale when there was a lower number of cases and restrictions had been eased (March to June 2022, the late group). Results In the early group, the EPDS scores were statistically higher(7.53.9 vs. 5.63.4; p < 0.001), smoking and NICU stay duration were significantly higher (p = 0.01), whereas the duration ofmarriagewas significantly lower (p = 0.01). Women in the late group with EPDS scores ≥13 were statistically less educated (p = 0.01). EPDS scores ≥13 were significantly associated with depression during pregnancy and with a history of abortion/stillbirth/neonatal death (odds ratio (OR) = 5.240, 95% confidence interval (CI) 1.114 to 27.967, p = 0.03 and OR = 1.641, 95% CI = 1.009 to 2.669, p = 0.04, respectively). Conclusions NICU admission is a significant maternal risk factor for postpartum depression due to the disruption of maternal-infant bonding, and this risk may be exacerbated during times of global public health crises such as the COVID-19 pandemic. Depression during pregnancy and the presence of a perinatal loss may also contribute to worse postpartum mental outcomes in NICU mothers.