Purpose <p>Xylazine, an α₂-adrenergic agonist developed as a veterinary sedative, has emerged as an adulterant in illicit opioid markets and is increasingly associated with morbidity and mortality. This systematic review synthesized observational evidence on xylazine exposure in fatal/mortality-related and non-fatal/morbidity-related human intoxication settings.</p> Methods <p>PubMed, Web of Science, the Cochrane Library, and Scopus were searched from inception through June 2025. Eligible studies included toxicologically confirmed, clinically suspected, surveillance-defined, pharmacovigilance-reported, or self-reported human xylazine exposure with fatal/mortality-related or non-fatal/morbidity-related outcomes. Findings were synthesized narratively because of heterogeneity in study design and outcomes.</p> Results <p>Twenty-eight studies met the inclusion criteria: twelve reported only non-fatal/morbidity-related data, fifteen reported only fatal/mortality-related data, and one reported both outcome categories. Non-fatal/morbidity-related exposure estimates ranged from 0.69% to 80.7%, reflecting different sampling frames and exposure definitions. Fatal/mortality-related studies used heterogeneous forensic, mortality, clinical, and pharmacovigilance denominators, limiting direct comparison. Where reported, deaths were usually accidental or unintentional overdose, although one large dataset reported most deaths as undetermined. Fentanyl was the dominant co-detected substance in fatal studies, with several reporting 98% to 100% co-detection. Reported postmortem blood xylazine concentrations were limited and heterogeneous, with study-level ranges extending approximately from 5 to 610 ng/mL.</p> Conclusion <p>Xylazine has been increasingly identified in predominantly U.S. clinical and forensic intoxication settings, usually with fentanyl co-exposure. Heterogeneity in study design, testing practices, denominators, and outcome reporting limits comparability and international applicability.</p>