Opioid misuse and dependence on prescribed opioids have strong link with drug addiction prevalence among adolescents. To gather evidence on the predictors of substance use, opioid abuse, and misuse of prescribed opioids, a systematic literature review was conducted covering articles published between 2016-2022. Of the 31 included articles, descriptively, substance use was considered as the dependent outcome in most of the studies (n = 15), compared to opioid misuse (n = 11), and prescription opioid misuse (n = 5). Resultantly, the common factors for substance use, opioid abuse, and misuse of prescribed opioids were broadly categorised into family-related factors, pain intensity and interference, comorbidity and psychopathology, demographic factors, substance use disorders and other drug addictive behaviours, and peer influence. Apart from the need to provide alternative pain management strategies, these factors should be considered by clinicians in identifying adolescents who are currently engaged in substance use or opioid abuse, and those likely to misuse prescribed opioids in the future.