Key PointsQuestionHow did US adult mortality rates due to external causes change between 1999 and 2020 by age, sex, race and ethnicity, and intent, and from 2019 to 2020 (after the onset of COVID-19)?FindingsIn this cross-sectional study of 3 813 894 deaths due to external causes, deaths from poisonings, firearms, and all other injuries increased between 1999 and 2020. From 2019 to 2020, death rates from each cause further accelerated, with the largest increases for deaths from unintentional poisoning and firearm deaths due to homicide.MeaningThe findings suggest that deaths due to external causes are increasing in the US.