We conducted a systematic review to examine the substance use and recidivism outcomes of prison-based substance use interventions. We searched public health, criminology, and psychology databases, and conducted forward and backward snowballing methods to identify additional studies. Studies were included if they were published between January 1, 2000 and June 30, 2017; were published in English; and reported substance use and/or recidivism outcomes of prison-based substance use interventions. Studies were reviewed for methodological rigor using the Effective Public Health Practice Project’s Quality Assessment Tool for Quantitative Studies. Our search returned 49 studies: 6 were methodologically strong, 20 were moderate, and 23 were weak. Results suggest therapeutic communities are effective in reducing recidivism and, to a lesser extent substance use after release. There is also evidence to suggest that opioid maintenance treatment is effective in reducing the risk of drug use after release from prison for opioid users. Furthermore, care after release from prison appears to enhance treatment effects for both types of interventions. Results provide evidence that policymakers can use to make informed decisions on best-practice approaches when addressing prisoner substance dependence and improving long-term outcomes. This comprehensive review highlights the difficulties of conducting quality research in the prison setting and suggests innovative study design for future research.