As the U.S. grapples with an opioid overdose epidemic, nurses are uniquely positioned to address the crisis through compassionate, ethical pain management and addiction prevention. This learning activity provides an in-depth overview of best practices for balancing chronic pain treatment with responsible prescribing and misuse prevention. Key topics include causes and impacts of the epidemic; CDC guidelines for risk screening prior to opioid therapy initiation; multimodal non-opioid approaches proving safer and more effective for persistent pain; signs of aberrant behaviors and opioid use disorders requiring assessment and intervention; and practical nursing strategies to curb risks including patient education, prescription drug monitoring program utilization, and attention to social determinants heightening vulnerabilities. Underpinned by a chronic disease model perspective, the learning activity aims to equip nurses with actionable knowledge and skills for tackling one of healthcare’s most urgent challenges while honoring patient-centered care.