ImportanceParents’ overdose death can have a profound short- and long-term impact on their children, yet little is known about the number of children who have lost a parent to drug overdose in the US.ObjectiveTo estimate the number and rate of children who have lost a parent to drug overdose from 2011 to 2021 overall and by parental age, sex, and race and ethnicity.Design, Setting, and ParticipantsThis was a cross-sectional study of US community-dwelling persons using data from the National Survey on Drug Use and Health (2010-2014 and 2015-2019) and the National Vital Statistics System (2011-2021). Data were analyzed from January to June 2023.ExposureParental drug overdose death, stratified by age group, sex, and race and ethnicity.Main Outcomes and MeasuresNumbers, rates, and average annual percentage change (AAPC) in rates of children losing a parent aged 18 to 64 years to drug overdose, overall and by age, sex, and race and ethnicity.ResultsFrom 2011 to 2021, 649 599 adults aged 18 to 64 years died from a drug overdose (mean [SD] age, 41.7 [12.0] years; 430 050 [66.2%] male and 219 549 [33.8%] female; 62 606 [9.6%] Hispanic, 6899 [1.1%] non-Hispanic American Indian or Alaska Native, 6133 [0.9%] non-Hispanic Asian or Pacific Islander, 82 313 [12.7%] non-Hispanic Black, 485 623 [74.8%] non-Hispanic White, and 6025 [0.9%] non-Hispanic with more than 1 race). Among these decedents, from 2011 to 2021, an estimated 321 566 (95% CI, 276 592-366 662) community-dwelling children lost a parent aged 18 to 64 years to drug overdose. The rate of community-dwelling children who lost a parent to drug overdose per 100 000 children increased from 27.0 per 100 000 in 2011 to 63.1 per 100 000 in 2021. The highest rates were found among children of non-Hispanic American Indian or Alaska Native individuals, who had a rate of 187.1 per 100 000 in 2021, more than double the rate among children of non-Hispanic White individuals (76.5 per 100 000) and non-Hispanic Black individuals (73.2 per 100 000). While rates increased consistently each year for all parental age, sex, and race and ethnicity groups, non-Hispanic Black parents aged 18 to 25 years had the largest AAPC (23.8%; 95% CI, 16.5-31.6). Rates increased for both fathers and mothers; however, more children overall lost fathers (estimated 192 459; 95% CI, 164 081-220 838) than mothers (estimated 129 107; 95% CI, 112 510-145 824).Conclusions and RelevanceAn estimated 321 566 children lost a parent to drug overdose in the US from 2011 to 2021, with significant disparities evident across racial and ethnic groups. Given the potential short- and long-term negative impact of parental loss, program and policy planning should ensure that responses to the overdose crisis account for the full burden of drug overdose on families and children, including addressing the economic, social, educational, and health care needs of children who have lost parents to overdose.