Key PointsQuestionWhat is the societal burden of unintentional opioid-related deaths in the US, and has it changed during the COVID-19 pandemic?FindingsIn this cross-sectional study of 422 605 unintentional deaths due to opioid toxicity, the years of life lost increased more than 3-fold, from 777 597 to 2 922 497, between 2011 and 2021. By 2021, 1 of every 22 deaths in the US was attributable to unintentional opioid toxicity.MeaningThe findings of this study suggest that public health impacts of opioid-related toxicity in the US are broad and have worsened during the pandemic, underscoring the urgent need to support people at risk of substance-related harm, particularly men, younger adults, and adolescents.