Objectives To investigate the association between the HLA-B*13:01 allele and dapsone hypersensitivity syndrome (DHS) in leprosy patients undergoing dapsone therapy. Methods A systematic review and meta-analysis were conducted following PRISMA guidelines. Databases, including MEDLINE, Embase, Cochrane, Scopus, and SpringerLink, were searched up to March 2025. Eligible studies were case-control or cohort designs reporting HLA-B*13:01 frequencies in DHS cases versus dapsone tolerant controls. Data extraction, quality assessment via the Newcastle-Ottawa Scale, and statistical synthesis using RevMan 5.4 were performed. Results Three eligible case-control studies were included, comprising 130 DHS cases, 1188 dapsone-tolerant leprosy patients, and 2040 healthy controls. A strong association was found between HLA-B13:01 and DHS, with a pooled OR of 82.28 [95% CI: 23.38–289.56]. HLA-B13:01 was present in 85.5%–91.2% of DHS cases compared to 3.85%–14.3% of dapsone-tolerant controls. Diagnostic accuracy was high, with sensitivity of 85.5%–91.2%, specificity of 85.7%–96.2%, and negative predictive values >97%. The AUC ranged from 0.89 to 0.95. Heterogeneity was moderate (I2 = 62%, P = 0.07), and all studies showed low risk of bias. Conclusions HLA-B*13:01 is strongly associated with DHS in leprosy patients. Its high diagnostic accuracy supports routine screening before dapsone initiation, particularly in endemic regions, to reduce the risk of severe hypersensitivity reactions. © 2025, Author.