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Background: Dengue and leptospirosis are prominent vector-borne diseases in tropical and subtropical regions, sharing overlapping geographic distribution and clinical presentations, which complicates diagnosis and management. Co-infection of these pathogens places additional strain on healthcare resources in endemic areas. This study aims to systematically estimate the prevalence and mortality rates of dengue and leptospirosis co-infections and assess their clinical implications. Methods: Adhering the PRISMA 2020 guidelines and registered in the PROSPERO database, we conducted a systematic review and meta-analysis using the PubMed, Embase, and Web of Science databases up to October 2024. Nested Knowledge was used for screening and data extraction. Studies reporting quantitative data on the prevalence or mortality of dengue and leptospirosis co-infections were included. Data extraction and quality assessment were performed independently by two reviewers using the Modified Newcastle-Ottawa Scale. Statistical analyses, including prevalence and mortality estimation, sensitivity analysis were conducted using R, with heterogeneity evaluated by the I² statistic. Results: Out of 3,982 records, 14 studies met the eligibility criteria, yielding a pooled prevalence of dengue and leptospirosis co-infection at 2.33% (95% CI: 1.41–3.46%) across 16,638 participants, with significant heterogeneity (I² = 90%). The prediction interval for co-infection ranged from 0.05 to 7.27%. The pooled mortality rate among co-infected patients was 9.96% (95% CI: 0–53.49%), with moderate heterogeneity (I² = 71%). The prediction interval for mortality ranged from 0.00 to 100%. Publication bias was indicated by an LFK index of 2.52. Conclusion: This meta-analysis revealed a moderate prevalence and a notable mortality rate for dengue and leptospirosis co-infections, with significant variability observed across different studies. Further research into the immunopathology and the implementation of integrated surveillance systems could enhance the effectiveness of diagnosis and treatment strategies in regions where these diseases are endemic. [ABSTRACT FROM AUTHOR]