The US is currently grappling with an escalating drug overdose crisis, with overdose deaths soaring to a record high of 110,000 in 2022 alone. This crisis has particularly devastating effects on African American, American Indian/Alaska Native and other racial/ethnic minority populations. Harm reduction strategies, such as naloxone distribution, are pivotal components of the US Department of Health & Human Services Overdose Prevention Strategy. While many jurisdictions across the country are actively expanding the availability of evidence-based harm reduction programs, the complexity of the overdose crisis necessitates a multifaceted and localized approach that goes beyond individual interventions. The availability of over $50 billion in legal opioid settlements nationwide, alongside innovative harm reduction interventions, such as overdose prevention centers, drug checking programs, and overdose detection technologies, presents unprecedented opportunities to address the overdose crisis and its harms comprehensively. Our project aims to design tailored harm reduction strategies that effectively address the heterogeneous nature of overdose epidemics, demographics, and local infrastructures across six distinct jurisdictions. Building on our previous work optimizing naloxone distribution strategies in Rhode Island, Massachusetts, and New York City, we will collaborate closely with health departments and community partners to assess the effectiveness, cost- effectiveness, and health equity outcomes of different harm reduction strategies in these and three new jurisdictions (Minnesota, Missouri, and Nevada). Through adapting a mathematical model and developing locally tailored decision tools, we will identify portfolios of harm reduction strategies that minimize fatal overdoses, maximize health equity, and provide value for money. Central to our approach is stakeholder engagement and the implementation of evidence-based interventions tailored to local contexts. By engaging relevant stakeholders in the adaptation and customization of our model and decision tools, we seek to ensure their integration into decision-making processes and their sustainability beyond the duration of our project. Furthermore, guided by implementation science, we will assess the fit and scalability of the model and decision tools in supporting data- and equity-informed policy decisions. This project will create urgently needed, publicly available evidence and resources that can guide the allocation of opioid settlement funds and inform the adoption of sustainable and scalable harm reduction strategies. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.