To decrease the high rates of mental health-related maternal morbidity and mortality among rural-dwelling women, it is critical to identify those experiencing postpartum depression (PPD) and provide necessary follow-up care. To effectively screen for PPD, clinicians must utilize instruments which account for context-specific factors and maintain validity across diverse populations. The Edinburgh Postnatal Depression Scale (EPDS) is the most commonly used depression screening tool in perinatal settings, but has not been validated for use within rural American settings. The aim of this study was to establish the psychometric properties of the EPDS and assess its validity for clinical use within a rural American context. In regards to construct validity, we found that a single-factor structure representing depression status was psychometrically sound and well explained by the items of the EPDS. The scale demonstrated strong criterion-related validity, where EPDS screening results were significantly correlated with the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria used by providers to make differential depression diagnoses. The EPDS yielded acceptable reliability and internal consistency (Cronbach's alpha = 0.90) in measuring depression status among our rural-dwelling sample. This is the first study establishing validity of a PPD screening tool within a rural U.S. population.