<p>Post-Kala-Azar Dermal Leishmaniasis (PKDL) is a chronic cutaneous sequela of Visceral Leishmaniasis (VL) that plays a critical role in disease transmission, particularly in endemic regions of South Asia and Africa. Despite global efforts to eliminate VL, PKDL remains a significant challenge due to its asymptomatic nature, delayed diagnosis, and limited treatment options. This systematic review aims to comprehensively analyse the immunopathogenesis, molecular diagnostics, and emerging therapeutic strategies for PKDL, with a focus on regional variations, diagnostic advancements, and treatment efficacy. A systematic literature search was conducted using databases including PubMed, Scopus, Web of Science, and Embase to identify studies published between 2000 and 2025. The study selection followed PRISMA guidelines, focusing on research related to PKDL pathogenesis, diagnostic methods (PCR, ELISA, histopathology), and treatment approaches such as Amphotericin B, Miltefosine, and multidrug regimens. PKDL pathogenesis involves complex immune responses, with increased levels of IL-10 and IFN-γ contributing to disease persistence. The disease manifests differently in South Asia (macular and polymorphic lesions) and Africa (predominantly macular). Diagnostic advancements, including qPCR and immunohistochemistry, enhance detection but require improved accessibility. Treatment strategies, including Liposomal Amphotericin B and Miltefosine, show varying efficacy, with combination therapies emerging as more effective alternatives. However, drug resistance, relapse, and adverse effects remain challenges. PKDL continues to be a major obstacle to VL elimination. While molecular diagnostics and combination therapies improve case management, further research is needed to develop more effective, accessible diagnostic tools and safer treatment regimens. Strengthening public health interventions, expanding treatment access, and exploring novel therapeutic targets are essential to achieving PKDL control and elimination.</p>