OBJECTIVES: To describe the 3-pronged approach taken by a large national retail pharmacy chain to address the opioid epidemic and associated overdoses. SETTING: Large national retail pharmacy chain with more than 8200 stores in 50 states. PRACTICE DESCRIPTION: Eight million customer interactions daily through in-store and digital settings. This is a company with a long history of responding to public health crises. PRACTICE INNOVATION: Initiated 3 programs to respond to the opioid crisis: 1) provide safe medication disposal kiosks; 2) expand national access to naloxone; and 3) provide education on the risk and avoidance of opioid overdose. Used the RE-AIM framework to evaluate and enhance the quality, speed, and public health impact of the interventions. EVALUATION: Not applicable. RESULTS: Early results are safe medication disposal kiosks in more than 43 states, naloxone-dispensing program in 33 states, and patient and support system education using the Opioid Overdose Toolkit from the Substance Abuse and Mental Health Services Administration. CONCLUSION: The availability of safe drug-disposal kiosks, naloxone dispensing at pharmacies, and patient education are key prevention initiatives to address the opioid epidemic and reduce the increasing national burden of opioid overdose. Early results are quantitatively and qualitatively promising.