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Background: Different techniques and approaches have been used for substance use prevention worldwide. No reviews of prevention interventions in Africa exist; hence this study aimed to systematically review interventions undertaken in Sub-Saharan Africa to prevent substance use in children and young people., Methods: MEDLINE, EMBASE, Cochrane Central, CAB, PsycINFO, CINAHL, SCOPUS, ERIC, and Web of Science databases were searched. Studies were included if they evaluated a substance use prevention intervention for children and young people in a Sub-Saharan African Country between 2000 and 2020. A narrative synthesis was used to explore and describe the data., Results: Eighteen studies, mostly from South Africa, were included. Most (10/18) of the interventions were school-based. Only two of the included studies were considered having a strong quality concerning the risk of bias, and some studies poorly reported the interventions. School-based interventions, although successful in improving knowledge, had little or no effects on substance use. Overall, most studies that reported a statistically significant reduction in substance use-related outcomes were brief interventions, individual-focused, and involved participants who were already exposed to substance use. These were mostly delivered by trained professionals using motivational interviewing or cognitive behavioural therapy or both., Conclusion: School-based programs present an opportunity for substance use prevention efforts in the Sub-Saharan region in Africa. Such programs may benefit from an improved focus on individual students. There is a need for improving the quality of design, implementation, and reporting of substance use interventions within the region., Competing Interests: Declarations of Interest The authors report no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)