Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with higher substance use rates. Stimulant and non-stimulant pharmacotherapy improve adolescent ADHD, but their associations with prescription stimulant misuse (PSM), cocaine, and methamphetamine use are unclear. Using 2005–2020 US Monitoring the Future data, we investigated relationships between ADHD pharmacotherapy history and PSM, cocaine, or methamphetamine use. Methods: Secondary students (13–19 years) provided data on pharmacotherapy history (N = 199,560; 86.3% of total sample) between January 1, 2005 and May 31, 2020 in a cross-sectional multi-cohort study; weights assured a nationally representative sample. Participants were grouped by ADHD pharmacotherapy history: none (88.7%; principally non-ADHD controls); stimulant-only (5.8%); non-stimulant-only (3.3%); both stimulant and non-stimulant (2.1%). Outcomes were past-year PSM, cocaine, and methamphetamine use. Logistic regressions examined relationships between pharmacotherapy history and outcomes, controlling for sociodemographics, recent substance use, and stimulant treatment cessation. Findings: Past-year outcome rates were lowest in adolescents with no pharmacotherapy history: 4.7% for PSM 8310/174,561, 1.6% for cocaine 2858/174,688, and 0.7% for methamphetamine 1036/148,378. A history of both stimulant and non-stimulant treatment was associated with the highest rates: 22.3% for PSM 940/4098, 10.4% for cocaine 450/4110, and 7.8% for methamphetamine 275/3427. Adolescents who received monotherapy (stimulant- or non-stimulant-only) had intermediate rates, with no differences between monotherapy groups. Interpretation: While elevated PSM and illicit stimulant use rates are likely influenced by ADHD, our findings suggested adolescents with a history of both stimulant and non-stimulant pharmacotherapy are at highest risk for these stimulant outcomes. Adolescents receiving ADHD pharmacotherapy should be monitored for PSM and illicit stimulant use. Funding: National Institute on Drug Abuse/National Institutes of Health (USA) and Food and Drug Administration (USA).