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Substance use continues to be a major public health problem for the low- and middle-income countries (LMICs) around the world. Prevention strategies, which are theoretically grounded, culturally sensitive, and cost effective, can help such resource-constrained nations mount effective control measures against drug use. Multisectorial involvement and multistakeholder participation can result in the development of sustainable prevention programs which earn long-term benefits for the nation. This narrative review looks into the various principles of primary prevention in drug use disorders and discusses the merits and effectiveness of varied intervention strategies used for universal, selective, or targeted prevention of drug use. Although evidence for effectiveness exists for various prevention programs in high-income countries (HICs), research from the developing world remains scarce. This paper focuses specifically on strategies which have found usefulness in other LMICs and interprets interventions from HICs in light of such findings. Policy-based programs, population interventions, community efforts, and treatment strategies are discussed to understand best pathways for prevention in various settings.