Alcohol, tobacco, and other drug (ATOD) use by adolescents are major contributors to death and disability in sub-Saharan Africa (SSA). This paper reviews the extent of adolescents' ATOD use, risk and protective factors, and studies evaluating prevention interventions for adolescents in SSA. It also describes the harms associated with adolescents' ATOD use in SSA, which mainly include interpersonal violence, sexual risk behaviours, and negative academic outcomes. We use the socio-ecological model as our framework for understanding ATOD use risk and protective factors at individual, interpersonal, peer/school, and societal/structural levels. We used two strategies to find literature evaluating ATOD interventions for adolescents in SSA: (a) we sought systematic reviews of adolescent ATOD interventions in SSA covering the period 2000-2020; and (b) we used a comprehensive evidence review strategy and searched for studies that had evaluated ATOD interventions in all SSA countries between 2000 and 2020. Only two community interventions (a brief intervention and an HIV prevention intervention), out of four that were identified, were partially effective in reducing adolescent ATOD. Furthermore, only one school-based intervention (HealthWise), out of six that we uncovered, had any effect on ATOD use among adolescents. Possible reasons why many interventions were not effective include methodological limitations, involvement of non-evidence-based education-only approaches in some studies, and shortcomings in adaptations of evidence-based interventions. The scale of ATOD and related problems is disproportionate to the number of evaluated interventions to address them in SSA. More ATOD interventions need to be developed and evaluated in well-powered and well-designed studies.