The Edinburgh Postnatal Depression Scale (EPDS) is used extensively as the “gold standard” perinatal depression and anxiety screening tool. This study contributes to an emerging discussion about the tool’s shortcomings, specifically around cultural suitability for use with Indigenous women. A systematic search was conducted in ProQuest, PsycINFO, MEDLINE (Web of Science), PubMed, Scopus, Informit, and CINAHL research databases, and grey literature. The quality of the body of evidence was assessed using the NHMRC Level of Evidence framework. Three studies supported the cultural validation of the EPDS with Indigenous groups in Canada (n = 2) and the USA (n = 1). The remaining eleven Australian studies demonstrated that cultural concerns were suggested by either Indigenous mothers, healthcare professionals (Indigenous and non-Indigenous), or both, though cultural concerns were more weighted from the perspectives of healthcare professionals. The quality of the evidence was not strong, and thus, there is a critical and urgent need for targeted research in this area. This review identified and recommended Indigenous-specific methodologies that can be adopted for more trustworthy, culturally safe, and effective research in this area. Given that the EPDS is currently considered gold standard in routine perinatal mental health screening practice in countries around the world, these findings raise significant concerns. Using culturally relevant research methodologies, such as the use of mixed-methods design, could lay stronger groundwork for further investigation of the broader utility and cultural relevance of the tool.