The increasing presence of xylazine, a veterinary tranquilizer, in the illicit opioid supply across the United States has intensified the public health burden of overdose mortality. Commonly referred to as “tranq,” xylazine is frequently combined with fentanyl, complicating clinical management due to its non-opioid pharmacological profile and unresponsiveness to naloxone reversal. Its physiological effects including profound central nervous system depression, hypotension, and vasoconstriction contribute to unique clinical presentations such as non-healing skin ulcers, rapid tissue necrosis, and bloodstream infections. These effects are particularly devastating among high-risk populations, including individuals experiencing homelessness, polysubstance use, and untreated psychiatric disorders. This systematic review synthesizes current data from toxicological studies, surveillance reports, and public health literature to examine the mechanisms, health impacts, and research gaps related to xylazine-fentanyl co-use. Our analysis highlights a pressing need for targeted surveillance, the development of clinical antagonists, and the expansion of housing-integrated harm reduction frameworks to address this evolving drug crisis.