Background <p>Pyrexia of Unknown Origin (PUO), also referred to as Fever of Unknown Origin (FUO), remains a persistent diagnostic challenge in clinical practice. In South Asian regions, endemic infections, resource constraints, variable diagnostic capacity, and heterogeneous clinical practices may further complicate evaluation. This systematic review aimed to synthesize the available evidence on the etiology, diagnostic approaches, reported management practices, and systemic barriers related to PUO in the region to inform improved clinical guidelines and health policies.</p> Methods <p>A systematic literature search was conducted in major electronic databases following PRISMA 2020 guidelines and registered in PROSPERO (CRD420251170142). Observational studies and large case series reporting PUO among all populations in South Asian countries were included. Dual independent screening, data extraction, and quality assessment were performed. Risk of bias was evaluated using the Joanna Briggs Institute (JBI) tools for observational studies and QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) for diagnostic accuracy studies. Findings were synthesized narratively due to substantial clinical and methodological heterogeneity.</p> Results <p>Thirty-seven studies were included, with infectious diseases predominating, most commonly tuberculosis, enteric fever, and scrub typhus. Non-infectious inflammatory diseases and malignancies accounted for significant minorities. Diagnostic yield varied substantially across studies, with higher yields reported in settings with greater access to advanced diagnostic modalities. Key systemic barriers included limited laboratory and imaging capacity, high rates of empirical antimicrobial use, absence of standardized diagnostic protocols, and patient-related factors like late presentation and cost. Reported management frequently involved empirical use of third-generation cephalosporins and doxycycline. Evidence was geographically imbalanced and India-dominant, with approximately 54% of included studies originating in India and nearly all conducted in tertiary hospital settings.</p> Conclusions <p>Available evidence suggests that PUO in South Asia is heterogeneous, with infections, particularly tuberculosis and other endemic infections, most frequently reported. Findings should be interpreted cautiously because studies were dominated by Indian tertiary-care settings and varied in definitions, diagnostic capacity, and confirmation criteria. Future research should prioritize standardized PUO definitions, transparent diagnostic-confirmation categories, prospective multicenter studies in underrepresented settings, and validated resource-stratified diagnostic pathways. Pragmatic early referral thresholds, such as persistent fever for 7–14 days without diagnosis after initial evaluation, may be explored in low-resource settings but require prospective validation.</p>