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Background and Objectives: Treating substance use disorder (SUD) in patients with co‐occurring attention deficit hyperactivity disorder (ADHD) and SUD may lower medical, psychiatric, and social complications. We conducted a systematic review with meta‐analysis to investigate the clinical benefits of pharmacological interventions to treat SUD in patients with ADHD. Methods: Articles were searched on Cochrane Central Register of Controlled Trials, PubMed, EBSCO, Google Scholar, Embase, Web of Science, and Ovid MEDLINE from 1971 to 2020. Data for SUD treatment as primary study endpoints and ADHD symptoms management as secondary outcomes were synthesized using random‐effects model meta‐analysis. Studies (N = 17) were included. The principal measure of effect size was the standardized mean difference (SMD). PROSPERO registration: CRD42020171646. Results: The pooled effect of pharmacological interventions compared with placebo was small for the reduction in substance use (SMD = 0.405, 95% confidence interval [CI]: [0.252, 0.557], P <.001), abstinence (SMD = 0.328, 95% CI: [0.149, 0.507], P <.001), craving (SMD = 0.274, 95% CI: [0.103, 0.446], P =.002), and the reduction in the frequency of ADHD symptoms (SMD = 0.420, 95% CI: [0.259, 0.582], P <.001). The pooled effect was moderate for the management of withdrawal symptoms (SMD = 0.577, 95% CI: [0.389, 0.764], P =.001]) and the decrease in the severity of ADHD symptoms (SMD = 0.533, 95% CI: [0.393, 0.672], P <.001). Conclusion and Scientific significance: The magnitude of benefits for pharmacological interventions varies. Despite some limitations, it was positive. This meta‐analysis is the first to appraise the benefits of medications to treat SUD in ADHD. It is the groundwork for treatment and risk mitigation. (Am J Addict 2020;00:00–00) [ABSTRACT FROM AUTHOR]