From 2019 to 2021, opioid-related deaths in Canada increased significantly, with the annual number rising from 3,007 to 6,222, and years of life lost (YLL) increasing from 126,115 to 256,336. The burden of premature opioid-related deaths doubled, representing over 250,000 YLL in 2021, or 1 in every 31 deaths among people under 85. The proportion of all deaths attributable to opioids increased across all age groups, with 29.3% and 29.0% of deaths among those aged 20–29 and 30–39 years, respectively, in 2021. The highest YLL was observed among males and young adults aged 20–39 years. The pandemic exacerbated the opioid crisis, with a significant increase in opioid-related deaths linked to the pandemic-related state of emergency. The shift to fentanyl-related deaths in provinces like Manitoba and Saskatchewan reflects a more volatile drug supply. The study highlights the need for targeted harm reduction programs, including improved access to drug-checking services, supervised consumption sites, and treatment for substance use disorders. The findings underscore the urgent need for public health responses to address the growing opioid crisis, particularly among males and younger adults. The study also notes that the burden of opioid-related deaths was higher than other leading causes of death in Canada for people under 85. Limitations include the exclusion of data from provinces with small counts and the potential underestimation of the total burden due to ongoing investigations. The study emphasizes the importance of expanding harm reduction efforts and improving access to safer opioid supply programs.From 2019 to 2021, opioid-related deaths in Canada increased significantly, with the annual number rising from 3,007 to 6,222, and years of life lost (YLL) increasing from 126,115 to 256,336. The burden of premature opioid-related deaths doubled, representing over 250,000 YLL in 2021, or 1 in every 31 deaths among people under 85. The proportion of all deaths attributable to opioids increased across all age groups, with 29.3% and 29.0% of deaths among those aged 20–29 and 30–39 years, respectively, in 2021. The highest YLL was observed among males and young adults aged 20–39 years. The pandemic exacerbated the opioid crisis, with a significant increase in opioid-related deaths linked to the pandemic-related state of emergency. The shift to fentanyl-related deaths in provinces like Manitoba and Saskatchewan reflects a more volatile drug supply. The study highlights the need for targeted harm reduction programs, including improved access to drug-checking services, supervised consumption sites, and treatment for substance use disorders. The findings underscore the urgent need for public health responses to address the growing opioid crisis, particularly among males and younger adults. The study also notes that the burden of opioid-related deaths was higher than other leading causes of death in Canada for people under 85. Limitations include the exclusion of data from provinces with small counts and the potential underestimation of the total burden due to ongoing investigations. The study emphasizes the importance of expanding harm reduction efforts and improving access to safer opioid supply programs.