Introduction <p>Dexmedetomidine has been used to treat toxicologic conditions, but high-quality data on its use for this indication in the emergency department setting are lacking. We sought to characterize the use of dexmedetomidine in this context.</p> Methods <p>We conducted a dual-center retrospective cohort study of patients treated with dexmedetomidine in two academic emergency departments. We included patients who received dexmedetomidine in the emergency department and had a toxicologic condition, as adjudicated by a medical toxicologist on chart review. We abstracted data from the electronic medical record. We conducted multilevel logistic regression to explore factors associated with intubation after the initiation of dexmedetomidine.</p> Results <p>We screened 1,081 patients and included 320. The most common toxicologic conditions were ethanol withdrawal (20%) and acute poisoning by sympathomimetics (19.7%). Culprit xenobiotics were primarily ethanol and substances of misuse. Median nadir heart rate and mean arterial pressure after dexmedetomidine initiation were normal, and there was no substantial change in nadir hemodynamic parameters after dexmedetomidine administration, although there was an increase in vasopressor administration (6.6% to 11.9%). Among patients who were not intubated when dexmedetomidine was initiated (<i>n</i> = 200), the frequency of intubation was 21.5% (95% CI 16–28). On multilevel logistic regression, antipsychotic administration was associated with increased odds of intubation (adjusted odds ratio 2.52, 95% CI 1.15–5.51).</p> Conclusion <p>Dexmedetomidine was primarily used to treat emergency department patients with intoxication or withdrawal from ethanol and substances of misuse. The frequency of intubation in spontaneously breathing patients after the initiation of dexmedetomidine was 21.5%. Further prospective research is needed to evaluate dexmedetomidine in the treatment of toxicologic conditions.</p>