Drug overdose deaths in the USA have increased rapidly in the past 20 years, and understanding patterns and trends in mortality is essential to develop policy responses. This study aimed to determine whether cohort patterns in mortality due to drug overdose have changed in the past two decades and assess these patterns by race and sex. The national records of accidental drug overdose death were extracted from Centers for Disease Control and Prevention, National Center for Health Statistics Mortality Data for 2000-2020. Age-period-cohort analysis was performed to examine independent effects of age, period and birth cohort on accidental drug overdose mortality. The number of accidental drug overdose deaths increased by 622% between 2000 and 2020, and age-standardized mortality rates increased nearly four-fold in both men and women. Age-period-cohort decomposition found rapid increases in mortality since 2012 in men and women, with higher mortality risk in cohorts born after 1990. The fastest increase occurred in Black Americans since 2012, and Americans of all races born after 1975 had significantly higher mortality risk, with mortality risk increasing rapidly in more recent cohorts. The peak of mortality has shifted from the 40-59 age group to the 30-40 year age group in the past decade. The burden of drug overdose mortality has shifted to younger Americans, and a new generation of Americans are at significantly higher and rapidly increasing risk of overdose death. Urgent action is needed to prevent an entire generation of young people being consigned to decades of preventable mortality. None.