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Background and Objectives: Postpartum depression (PPD) is a prevalent mental health condition with substantial consequences for mothers, infants, and families. The Edinburgh Postnatal Depression Scale (EPDS) is the most widely used screening instrument for PPD; however, optimal cut-off scores vary across populations, necessitating local validation. No prior study has evaluated the diagnostic performance of the EPDS against a structured clinical interview in Latvia. To assess the reliability and diagnostic accuracy of the Latvian version of the EPDS and to determine the optimal cut-off score for detecting PPD in a Latvian outpatient population 4-6 weeks after childbirth. Materials and Methods: A cross-sectional study was conducted at the outpatient department of Riga Maternity Hospital between June 2024 and May 2025. Women aged ≥18 years attending routine postnatal check-ups were screened using the Patient Health Questionnaire-9 (PHQ-9). Those scoring ≥5 were invited to complete the EPDS and participate in a structured diagnostic interview using the Mini International Neuropsychiatric Interview (MINI) 7.0.2. Internal consistency was assessed using Cronbach's alpha. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic accuracy and identify the optimal cut-off score based on sensitivity, specificity, likelihood ratios, and the Youden Index. Results: A total of 272 women were screened, and 101 completed the EPDS; 78.63% of screen-positive participants underwent the MINI. The EPDS demonstrated excellent internal consistency (Cronbach's α = 0.871). ROC analysis indicated strong discriminative ability (AUC = 0.852, 95% CI 0.759-0.945, p < 0.001). A cut-off score of ≥11 provided the optimal balance between sensitivity (0.74) and specificity (0.82), with the highest Youden Index (0.56) and a positive likelihood ratio of 4.14. Conclusions: The Latvian version of the EPDS is a reliable and diagnostically accurate screening instrument for PPD 4-6 weeks after delivery. A cut-off score of ≥11 appears optimal for routine screening in Latvian outpatient settings. These findings support the integration of EPDS-based screening into structured postpartum care and underscore the value of validating screening instruments within specific cultural and clinical contexts.