Background: The opioid epidemic has created unprecedented challenges in the United States (US), including hundreds of thousands of lives lost to overdose in the past five years. Expansion of prevention and treatment for opioid use disorder (OUD) is urgently needed, as evidence-based strategies exist but many remain unable to access life-saving services. Purpose: To inform school health and mental health providers, educators and school administrators about the causes and consequences of the US opioid epidemic and to provide practical solutions for engineering multi-tiered systems of support for children and families affected by the epidemic, including through opioid misuse, OUD, and opioid overdose. Methods: We review the literature on the history of and current challenges associated with the opioid epidemic in the US. Results: The collateral damage of OUD is pervasive, impacting children and families across the US. We found no health education programs focusing on this topic in US schools, underscoring a critical need and cogent practice/policy avenue. Discussion: Schools are uniquely positioned to respond to the opioid epidemic, but school health and mental health providers, educators, and other professionals who work in schools must have accurate knowledge of the opioid epidemic, understand the challenges it is causing for children and families, and be familiar with best practices in prevention and treatment. Translation to Health Education Practice: This review provides a succinct overview of the history of the opioid epidemic, examines its impacts on children and families, and provides a call to action for schools to partner in our national response.