Key PointsQuestionHow have opioid misuse prevalence trajectories changed for youths and young adults by birth cohorts in the US from 2002 to 2019?FindingsIn this cross-sectional study of 114 412 participants, the trajectories of opioid misuse in youths and young adults improved based on cross-sectional pseudocohorts beginning in 2002, 2005, 2008, 2011, and 2014. Most notably, during high school years, later pseudocohorts had lower starting prevalence rates, and the rates increased less sharply with age.MeaningThese findings describing pseudocohort prevalence rates for opioid misuse, including a decrease in opioid misuse in high school years in recent pseudocohorts, may provide insight into behaviors that affect drug use trends among youths and young adults in the US household population.