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. Lay Abstract Symptoms characteristic of autism spectrum disorder were initially believed to protect individuals with autism spectrum disorder from developing substance abuse. However, recent studies suggest that up to 36% of individuals with autism spectrum disorder may have a co-occurring issue with substance abuse. In addition, substance abuse may worsen the difficulties with daily functioning some individuals with autism spectrum disorder experience. It is important to understand occurrence rates, and risk, protective and positive treatment factors of co-occurring autism spectrum disorder and substance abuse in order to promote the best possible support for this special population. This review aimed to find and synthesize evidence regarding risk, protective and treatment factors, and determine a general prevalence rate of co-occurring autism spectrum disorder and substance abuse from all studies on substance use and abuse in individuals with autism spectrum disorder. The review also aimed to assess study quality and identify a diagnostic measure for substance abuse in individuals with autism spectrum disorder. Twenty-six studies on substance use and abuse in autism spectrum disorder were included in the review. The rates of substance abuse among those with autism spectrum disorder identified by included studies ranged from 1.3% to 36%, but due to large differences in study methods, a general prevalence rate could not be determined. Risk and protective factors, recognized in the general population, such as familial substance abuse and co-occurring mental health issues, and factors which may be more likely to occur in individuals with autism spectrum disorder, such as limited social resources and low sensation-seeking, were identified. No diagnostic measures specific to individuals with autism spectrum disorder and substance abuse were identified. This review identified only one exploratory study on an adapted intervention for co-occurring autism spectrum disorder and substance abuse. However, there were many methodological challenges in this study that limit the conclusions that can be drawn from the data. More research, using consistent methods, is needed to understand risk and protective factors and to determine the prevalence of substance abuse among individuals with autism spectrum disorder. The potential for co-occurring autism spectrum disorder and substance abuse should be considered by professional working in both autism spectrum disorder and substance abuse services, as finding suggests substance abuse is possible among individuals with autism spectrum disorder and may occur more frequently than previously believed. In addition, autism spectrum disorder and substance abuse service providers should be sensitive to specific risk and protective factors identified by the review that may impact substance abuse course and outcomes.