Background <p>Postpartum depression (PPD) is known to be prevalent and debilitating among most populations of new mothers worldwide. Despite its historic impact on maternal mental health and child development, the underlying neuroendocrine mechanisms remain poorly understood.</p> Aim <p>This review aims to provide a comprehensive analysis of the neuroendocrine mechanism underlying postpartum depression by integrating the current knowledge on the role of perinatal neuroendocrine dysregulation in the pathophysiology of postpartum depression with emerging therapeutic opportunities derived from some of these mechanistic insights.</p> Methods <p>A scientific search of databases such as PubMed, Scopus, and Google Scholar for studies published from January 2000 to January 2024 was conducted. Articles were selected based on relevance to perinatal postpartum depression, PPD pathophysiology, therapeutic applications, including pre-clinical and clinical studies.</p> Results <p>The search identified key dysregulated pathways, including HPA axis dysregulation, neurotransmitter adaptations, rapid hormonal fluctuations, and altered oxytocin signalling. Recent understanding of these networks of interaction has influenced novel therapeutic approaches, such as neuroactive steroid-based treatments.</p> Conclusion <p>This review provides insights into potential biomarkers for early detection and individualized treatment strategies, while also highlighting areas requiring further investigation to optimize therapeutic outcomes for PPD.</p>