Background and Objectives The involvement of xylazine, a veterinary drug, in West Virginia (WV) human drug‐related deaths was examined. Methods WV drug deaths from 2019 (when xylazine was first identified) to mid‐2021. Characteristics including toxicology findings were compared between xylazine and nonxylazine deaths. Results Of 3292 drug deaths, 117 involved xylazine, and the proportions of deaths with it have increased (1% [2019] to 5% [mid‐2021)]. Xylazine decedents had more cointoxicants, with fentanyl (98%) predominant followed by methamphetamine. Xylazine decedents had a significantly greater history of drug or alcohol misuse and hepatic disease. Conclusions and Scientific Significance In one of the largest analyses of xylazine‐involved deaths in a predominantly rural state, identification of xylazine was increasing with multiple cointoxicants (especially fentanyl), and was present in a few deaths with only one other substance involved. Health professionals should be aware of possible enhanced toxicity from xylazine ingestion especially since naloxone does not reverse xylazine's adverse effects.