Deaths of parents and grandparent caregivers threaten child well-being owing to losses of care, financial support, safety and family stability, but are relatively unrecognized as a public health crisis. Here we used cause-specific vital statistics death registrations in a modeling approach to estimate the full magnitude of orphanhood incidence and prevalence among US children aged 0–17 years between 2000 and 2021 by cause, child age, race and ethnicity, sex of deceased parent and state, and also accounted for grandparent caregiver loss using population survey data. In 2021, we estimate that 2.91 million children (4.2% of children) had in their lifetime experienced prevalent orphanhood and caregiver death combined, with incidence increasing by 49.5% and prevalence by 7.9% since 2000. Populations disproportionately affected by orphanhood included 5.2% of all adolescents; 6.4% and 4.7%, respectively, of non-Hispanic American Indian or Alaska Native, and non-Hispanic Black children; and children in southern and eastern states. In 2021, drug overdose was the leading cause of orphanhood among non-Hispanic white children, but not among minoritized subgroups. Effective policies and programs to support nearly three million bereaved children are needed to reduce the acute and long-term negative effects of orphanhood.