Background: Postpartum Depression (PPD) develops within the first few weeks or months following delivery and causes severe emotional and psychological problems. Pain has been closely linked to the occurrence of depression. Observational studies have suggested that effective pain relief during childbirth can reduce the incidence of PPD. However, these studies are fraught with numerous confounding factor. Combined Spinal-Epidural Analgesia (CSEA) is a commonly used pain relief method during childbirth. It is currently unclear whether a causal relationship exists between CSEA and PPD. Methods: An analysis was conducted using five methods in Mendelian randomization (MR) to study the use of CSEA during childbirth and PPD. The data were obtained from the United Kingdom Biobank Database (UKB) for CSEA and from FinnGen for PPD. The analysis included MR Egger, weighted median, Inverse Variance Weighted (IVW), simple mode, and weighted mode. We then conducted exposure heterogeneity testing using Cochran’s Q statistics and assessed the pleiotropy of exposure Single Nucleotide Polymorphisms (SNPs) using MR-Egger. Results: IVW Odds Ratio (OR): 0.978, 95% confidence intervals (95%CI): 1.031–0.407, P: 0.408. The results of the weighted median (OR: 1.035, 95% CI: 0.995, 1.118, P: 0.377), simple mode (OR: 0.929, 95% CI: 0.773, 1.116, P: 0.435), and weighted mode (OR: 0.995, 95% CI: 0.930, 1.065, P: 0.888) suggest that there is no significant link between CSEA and PPD. Conclusion: We have concluded that there is no causal link between CSEA and PPD. This information can assist clinical professionals in gaining a better understanding of this condition.