Background: Adolescent substance use is a continued public health concern. The objective of this manuscript is to detail the prevalence of substance use, polysubstance use, and investigate sex differences in the Adolescent Brain Cognitive Development (ABCD) Study from ages 9–17. Methods: 11,880 youth across the U.S., recruited at ages 9–10, completed annual study visits from September 2016 to January 2024. The ABCD 6.0 data release comprises baseline to year-6 data. Lifetime and annual substance use prevalence rates, sex differences, and polysubstance use are described and analyzed. Results: Past-year substance use prevalence increased with age; 38% report lifetime use by age 16. Alcohol, cannabis, and nicotine were the most reported substances. There were non-significant differences observed between unweighted trends and census-weighted trends. More boys reported substance use prior to age 12, then from age 13 onward, more girls reported use. Polysubstance use analyses detail the occurrence of the most shared substance use patterns and divergent reports across the sexes. Conclusions: Descriptively, these prevalence rates mirror other national surveys showing increases in reported use across early adolescence, with alcohol, cannabis, and nicotine being the most used substances. Unique sex differences and polysubstance use prevalence rates are contextualized alongside prior national reports of these behaviors in the U.S. Understanding the latest prevalences, specifically in a well-phenotyped cohort, helps to guide knowledge for continued analysis of antecedents and sequelae of substance use on health.