A revised way of thinking is essential for promoting harm reduction strategies and reducing the negative implications of injection drug use (IDU). Despite the growth of harm reduction approaches in the United States, there is limited guidance for designing and implementing multi-sector efforts that address the external determinants that promote and facilitate IDU. Current frameworks fail to acknowledge the individual's role and influence in multi-sector change. To address the multifaceted nature of IDU, we must address the complex relationship between people who inject drugs (PWID) and their external environment. As part of a community-academic partnership, a framework was developed to address the gaps in current theoretical models and community practice. Our Harm Reduction Collaboration Framework (HRCF) accepts PWID as key stakeholders and presents a practical framework in which PWID and community organizations partner in decision making to influence policy, systems, and environmental change. We provide examples of two organizations that have made substantive changes in implementing harm reduction strategies in their communities by utilizing the HRCF.