This review aims to examine prescribed short-term opioid use in adolescents to treat acute pain. The review will analyze the influence of opioid use on future non-medical opioid use (misuse) or substance use disorders (addiction) in adolescents and young adults. Prescription opioids are medically indicated for acute pain. Descriptive studies of administrative datasets and surveys implicate adolescent opioid exposure as a risk factor for subsequent opioid misuse and addiction. This review will provide a synthesis of the literature on the association between prescribed opioid exposure to treat acute pain in adolescents and the subsequent development of opioid misuse or substance use disorders in adolescents and young adults. This review will consider quantitative studies on opioid misuse or substance use disorders in Canadian and US adolescents and young adults (12 to 25 years of age). Studies must include exposure during adolescence (12 to 17 years of age) to legitimately prescribed short-term opioid use to treat acute pain. Studies on chronic pain or exposure to opioids for longer duration (more than 30 doses or more than 7 days) will be excluded. This review will follow the JBI methodology for systematic reviews of etiology and risk. Published and unpublished studies will be sourced from multiple databases and resources. Two independent reviewers will screen, appraise, and extract data from studies that meet the inclusion criteria. Data synthesis will be conducted and a Summary of Findings will be presented. PROSPERO CRD42020179635.