ObjectivesDespite the widespread use of prescription benzodiazepines, there are few studies examining trends and patterns of benzodiazepine-related toxicity. We describe the epidemiology of benzodiazepine-related toxicity in Ontario, Canada.MethodsWe conducted a population-based, cross-sectional study of Ontario residents who had an emergency department visit or hospitalization for benzodiazepine-related toxicity between January 1, 2013 and December 31, 2020. We reported annual crude and age-standardized rates of benzodiazepine-related toxicity overall, by age, and by sex. In each year, we characterized the history of benzodiazepine and opioid prescribing among people who experienced benzodiazepine-related toxicity, and reported the percentage of encounters with opioid, alcohol, or stimulant co-involvement.ResultsBetween 2013 and 2020, there were 32,674 benzodiazepine-related toxicity encounters among 25,979 Ontarians. During this period, the crude rate of benzodiazepine-related toxicity declined overall, from 28.0 to 26.1 per 100,000 population (age-standardized rate: 27.8 to 26.4 per 100,000), but increased among young adults aged 19 to 24 (39.9 to 66.6 per 100,000 population). Moreover, by 2020, the percentage of encounters associated with active benzodiazepine prescriptions had declined to 48.9%, while the percentage of encounters that had opioid, stimulant, or alcohol co-involvement rose to 28.8%.ConclusionBenzodiazepine-related toxicity has declined in Ontario overall, but has increased among youth and young adults. Furthermore, there is growing co-involvement of opioids, stimulants, and alcohol, which may reflect the recent emergence of benzodiazepines in the unregulated drug supply. Multifaceted public health initiatives comprising harm reduction, mental health supports, and promotion of appropriate prescribing are needed to reduce benzodiazepine-related harm.Supplementary InformationThe online version contains supplementary material available at 10.17269/s41997-023-00784-3.