Importance: Emerging evidence suggests substance use may have fallen during the COVID-19 pandemic among U.S. adolescents. However, existing work has been characterized by short-term follow-up in the early phase of the pandemic, limited temporal resolution for assessing changes, and lack of investigation of how pandemic effects may vary across the population. Anticipating the longer-term impact of the pandemic on adolescent substance use requires prospective, longitudinal evidence that goes beyond a âone-size-fits-allâ characterization of the pandemicâs impact.Objective: Measure changes in substance use among early adolescents over the first 14 months of the COVID-19 pandemicDesign: Prospective, longitudinal, community-based cohort study with seven-wave assessment of substance use between May 2020 and May 2021, plus pre-pandemic assessments occurring in 2018-2019.Setting: 21 study sites in communities across the U.S.Participants: 9,270 youth ages 11-12 years old who were participants in the Adolescent Brain Cognitive DevelopmentSM Study. To improve generalizability, data were weighted to reflect the sociodemographic composition of the U.S. Census.Main Outcomes: Self-reported use of alcohol, nicotine, cannabis, and other substances.Results: Pandemic-related decreases in the prevalence of alcohol use were detectable in May 2020, grew larger over time, and remained substantial in May 2021. Pandemic-related increases in inhalant use and prescription drug misuse were detectable in May 2020, shrunk over time, and were smaller but still detectable in May 2021. Pandemic-related increases in nicotine use were detectable between May 2020 and March 2021 and no longer significantly different from pre-pandemic levels in May 2021. There was significant heterogeneity in the pandemicâs effect on substance use at some timepoints, with increased rates among youth identified as Black or Hispanic or in lower-income families versus stable or decreased rates among youth identified as White or in higher-income families.Conclusions and Relevance: Among a nationwide sample of 11-12 year-olds, rates of alcohol use remained dramatically reduced in May 2021 relative to pre-pandemic and rates of prescription drug misuse and inhalant use remained modestly increased. Differences remained despite partial restoration of pre-pandemic life, raising questions about whether youth who spent early adolescence under pandemic conditions may exhibit persistently different patterns of substance use.