Abstract Study objectives The main aim of this study was to estimate the association between sleep deficiency in adolescence and subsequent prescription opioid misuse in adulthood using United States nationally representative longitudinal data. Methods Self-reported data captured in the National Longitudinal Study of Adolescent to Adult Health at baseline (Wave 1; mean age = 16 years) and 12 year follow-up (Wave 4; mean age = 29 years). Participants (n = 12,213) reported on four measures of sleep during adolescence (Wave 1) and on lifetime prescription opioid misuse during adulthood (Wave 4). Associations between adolescent sleep and adult opioid misuse were estimated using multivariate logistic regression analysis controlling for sociodemographics, chronic pain, mental health, childhood adverse events, and a history of substance use. Results During adolescence, 59.2% of participants reported sleep deficiency. Prospectively, adolescents reporting not getting enough sleep, chronic unrestful sleep, and insomnia were associated with an increased risk for prescription opioid misuse (adjusted odds ratios OR = 1.2, p < 0.005 for all three variables). Short sleep duration was not associated with opioid misuse. Conclusion This is the first study to longitudinally link sleep deficiency as an independent risk factor for the development of prescription opioid misuse. Sleep deficiency could be a driver of the opioid crisis affecting young people in the United States. Future studies should determine whether early and targeted sleep interventions may decrease risk for opioid misuse in high-risk patients prescribed opioids for pain.