BACKGROUND Most coronavirus disease 2019 (COVID-19) deaths occur among adults, not children, and attention has focused on mitigating COVID-19 burden among adults. However, a tragic consequence of adult deaths is that high numbers of children might lose their parents and caregivers to COVID-19–associated deaths. METHODS We quantified COVID-19–associated caregiver loss and orphanhood in the United States and for each state using fertility and excess and COVID-19 mortality data. We assessed burden and rates of COVID-19–associated orphanhood and deaths of custodial and coresiding grandparents, overall and by race and ethnicity. We further examined variations in COVID-19–associated orphanhood by race and ethnicity for each state. RESULTS We found that from April 1, 2020, through June 30, 2021, >140 000 children in the United States experienced the death of a parent or grandparent caregiver. The risk of such loss was 1.1 to 4.5 times higher among children of racial and ethnic minority groups compared with non-Hispanic White children. The highest burden of COVID-19–associated death of parents and caregivers occurred in Southern border states for Hispanic children, in Southeastern states for Black children, and in states with tribal areas for American Indian and/or Alaska Native populations. CONCLUSIONS We found substantial disparities in distributions of COVID-19–associated death of parents and caregivers across racial and ethnic groups. Children losing caregivers to COVID-19 need care and safe, stable, and nurturing families with economic support, quality child care, and evidence-based parenting support programs. There is an urgent need to mount an evidence-based comprehensive response focused on those children at greatest risk in the states most affected.