American Indian/Alaska Native (AI/AN) populations have proven particularly susceptible to the opioid crisis in the USA, but the White Houses 2019 national opioid policy roadmap is not structured to address AI/AN vulnerabilities. The concept of resilience, usually considered a positive system attribute, can be applied to complex systems to understand the larger compensatory interactions that restore systems to previous structures despite disruptions or interventions. The opioid crisis is a case of detrimental resilience because even effective interventions have not succeeded in eradicating opioid abuses. Resilience-based systemic interventions are needed to disrupt various aspects of systems while enhancing the social and cognitive abilities of affected populations to withstand the threat. This paper examines community characteristics, healthcare, and law enforcement within the context of AI/AN populations to emphasize the mechanisms that promote undesirable resilience for the opioid crisis. A research agenda bringing together systems science and management is needed to coordinate sectoral interventions and establish strategies to disrupt the resilient cycle of opioid addiction.