Introduction Substance use in adolescents with disabilities is rising, containing the prevalence of substance-related disorders (SRD) such as addiction, mental or health disorders, cancer, accidents and mortality. Yet little is known about the existing substance use prevention programs among adolescents with dosabilities or physical impairments. The aim of this systematic review was to investigate the effects of school-based interventions or prevention programs directed at the reduction of alcohol, tobacco and drug use in young adolescents with disabilities or physical impairments. Method Five scientific databases were explored mainly for school-based randomized controlled trials (RCTs) and prevention programs examining the effects of substance use interventions and prevention programs on adolescents with disabilities or physical impairments. Guided by the NICE guidelines, eligible articles were detected from which data were collected. A systematic literature review was performed for many diverse outcomes such as, substance use knowledge, substance use, modelling social environment, intention to quit smoking, peer pressure, etc. Results The primary literature search resulted in 821 articles. Five studies were incuded in the systematic literature review. Most of the collected studies were about adolescents with intellectual disabilities (MBID or MMID). The review's sample group ranged from 12-to 18-year-old adolescents. Included studies had a total sample of 981 out of which 13 were teachers. Studies measured both primary and secondary outcomes like modelling smoking, substance use and frequency of alcohol use. Conclusion This review summarized evidence about interventions and prevention programs aimed at decreasing or preventing substance use in adolescents with various types of disabilities or physical impairments. Substance use education increases knowledge about alcohol, tobacco and drug use and the health-related harms in teenagers with disabilities. Additional research is required especially among teenagers with intellectual disabilities and other types of disabilities.