The field of nanomedicine offers revolutionary potential to reshape the discovery and development of therapeutics for diverse human diseases. However, its application has been limited in improving Substance Use Disorders (SUDs), which represent a profound public health crisis, including major types such as opioid, alcohol, stimulant, and cannabis use disorders. Pharmacotherapy, a cornerstone of SUD management, has reduced morbidity, mortality, and the societal impact of addiction, though its efficacy has ranged from none to moderate. Thus, there is a major unmet need to transform SUD pharmacotherapy to curb the epidemic of addiction. This article explores the potential roles of nanomedicine-inspired precision-targeted drug delivery, sustained release, and combination therapies to increase therapeutic efficacy and minimize side effects. Additionally, it discusses innovative mechanisms that align with the neurobiological complexities of addiction and synergistic approaches that integrate nanomedicine with behavioral interventions, device-based therapies, and emerging modalities such as immunotherapy and neurostimulation. Despite these advancements, barriers such as treatment accessibility, adherence challenges, and inequitable resource distribution persist, particularly in underserved populations. By harnessing the transformative capabilities of nanomedicine and integrating it into holistic, equitable, and personalized care frameworks, this review highlights a path forward to revolutionize the SUD pharmacotherapy landscape. The article underscores the need for continued nano-SUD pharmacotherapy research and the development of strategies to alleviate the substantial burden of addiction on individuals, families, and society.