Objectives: Postpartum depression (PPD) is a severe mental health disorder affecting a significant proportion of mothers, often undiagnosed and untreated, with potential long-term effects. While numerous studies have identified risk factors for PPD, the relationship between inflammatory markers and PPD remains unknown. This study aimed to investigate the potential correlation between indirect inflammatory markers, specifically neutrophil-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR), and the risk of developing PPD, assessed by the Edinburgh Postnatal Depression Scale (EPDS). Design: This was a prospective observational study conducted in a second-level university hospital, from December 2019 to February 2021. Participants: A total of 211 full-term pregnant women were enrolled. Exclusion criteria included specific psychiatric diagnoses, such as severe intellectual disability, schizophrenia, schizoaffective disorder, delusional disorder, bipolar or other unspecified psychotic spectrum disorders. Additionally, pregnancies affected by gestational and pregestational diabetes, chronic hypertension, gestational hypertension, preeclampsia/eclampsia, intrauterine fetal growth restriction, preterm delivery, multiple pregnancies, and fetal abnormalities detected prenatally were excluded. Methods: Socio-demographic and clinical data were recorded. Blood samples for complete blood count were obtained at hospital admission, focusing on NLR, PLR, and MLR. Analyses were conducted in our laboratory using standard techniques. The postpartum PPD evaluation was conducted 3 days after delivery, with the EPDS Italian version. Statistical analyses included descriptive statistics, group comparisons using t tests or Wilcoxon rank-sum tests for continuous variables, and Pearson χ2 or Fisher’s exact tests for categorical variables. Correlation analyses employed Pearson correlation or Spearman’s rank correlation tests. Simple logistic regression models, adjusted for various baseline patient characteristics, explored the correlation between inflammatory markers (PLR, NLR, MLR) and postpartum depressive symptoms. Version 4.1.3 of RStudio statistical software was utilized. Results: Overall, 211 pregnant women enrolled were categorized into two groups based on the EPDS scores: <10 (176 patients) and ≥10 (35 patients). The two groups demonstrated homogeneity in different socio-demographic factors. Stepwise regression analysis indicated that PLR, NLR, and MLR were not significantly associated with these variables. The scatterplot of PLR, NLR, and MLR on EPDS was stratified for EPDS groups. The Wilcoxon rank-sum test applied to PLR, NLR, and MLR values and EPDS groups did not reveal a statistical relationship. Additional analyses were conducted using the estimated odds ratios of the logistic regression model on EPDS groups, considering both continuous and binary values of indirect inflammatory markers (PLR, NLR, MLR). The results indicated the absence of a statistical relationship. Limitations: Our evaluation was restricted to the postpartum period, and data for the first and second trimesters of pregnancy are lacking. Conclusions: Our findings did not evidence a correlation between indirect inflammatory markers (NLR, PLR, and MPL) and PPD. This novel finding prompts further evaluation of the role of indirect inflammatory markers in PPD, highlighting the need for additional research to clarify the complex relationship between inflammation and psychological health in the postpartum period.