A systematic review of autism spectrum disorder and substance use and abuse was conducted based on the Preferred Reporting Items for Systematic Review and Meta-Analysis protocol guidelines (an internationally recognized standardized methodological framework for conducting systematic review). The objectives of the review were to update and extend findings reported by Arnevik and Helverschou's review of the autism spectrum disorder and substance use literature by (1) evaluating study quality via the Mixed-Methods Appraisal Tool; (2) examining autism spectrum disorder and substance abuse diagnostic measures; (3) reporting on the prevalence of co-occurring autism spectrum disorder and substance abuse; and (4) identifying risk, protective, and positive treatment factors. Twenty-six studies on substance use and abuse in autism spectrum disorder were identified through a search of MEDLINE, PsycINFO and Google Scholar. Average study quality score was 75.4%. Prevalence rates of substance abuse among samples with autism spectrum disorder ranged from 1.3% to 36%, but due to variability in sample characteristics and diagnostic measures, a general prevalence rate could not be established. Risk and protective factors, recognized in the general population, such as familial substance abuse and comorbid externalizing disorders, and factors, which may be more likely to occur in individuals with autism spectrum disorder compared to the general population, such as few social resources (i.e. sense of social belonging, breadth of social support networks, and level of social capital) and low sensation-seeking, were identified. One intervention study was identified; however, methodological limitations preclude any conclusion regarding positive treatment factors at this time. More research, using standardized measures and comparable samples, is needed to understand risk and protective factors and to determine the prevalence of co-occurring substance abuse and autism spectrum disorder.