The use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. Physicians, policymakers, and researchers are focused on finding ways to decrease opioid use and overdose. This crisis calls for a coordinated response that includes the entire healthcare sector. In this work, the authors lay out a blueprint for such a response at the level of the academic medical center. The proposed model is a comprehensive opioid overdose prevention, response, and education program to evaluate, monitor, and address prescription opioid-related adverse events and addiction among all patients within a healthcare system. The approach includes three inter-related elements: (1) creation of an organizational structure that is subdivided into subcommittees to facilitate cross-functional collaboration and implementation. These subcommittees will focus on Research and Design, Implementation, Advisory, and Compliance with the recommendation. (2) Development of an effective communication plan throughout the institution to enable the organization to function seamlessly and efficiently as a single unit, (3) development of a data tracking and reporting system that intended to have a 360° view of all aspects of opioid prescription and downstream patient outcomes. The most effective response system will require an organizational structure that facilitates the ad hoc constitution of cross-functional teams with members drawn from all levels of the organizational hierarchy (executive leadership to frontline staff). Such a structure provides the teams with immediate solutions as developed by the frontline staff and authority to remove institutional barriers that may delay or limit the successful implementation. The model described was developed in our institution by a cross-functional team that included members from the Johns Hopkins School of Medicine and Johns Hopkins University Carey Business School, Department of Operations Management. The multidisciplinary nature of collaboration allowed us to develop a model for an immediate institution-wide response to the opioid crisis, and one that other healthcare organizations could adopt with local modification as a template for execution. The model also meant to serve as a template for an institutional rapid-response that can be seamlessly implemented during any future drug-related crisis or epidemic.