Rapidly rising drug overdose rates in the United States during the past three decades underscore the critical need to prevent overdose deaths and reduce the development of opioid and related substance use disorders (SUDs). Traditional public health models of prevention emphasize the biological and physical risks of SUDs, often neglecting to consider the broader environmental and social factors that influence health and well-being. Taking a socioecological approach, the authors aim to illustrate the complex interplay among individual, interpersonal, societal, and structural factors that contribute to the development of SUD and overdose risk. The authors propose evidence-informed strategies and interventions across primary, secondary, and tertiary levels of prevention. By doing so, the authors hope to encourage policymakers, funders, service providers, and community leaders to broaden their approaches to SUD prevention and consider how they can create and advocate for a health-promoting environment by addressing the social and structural factors that drive rising SUD and overdose trends.