Prescription opioid (POs, i.e. opioid analgesics requiring a prescription) related harms are extensive in North America; non-medical PO use (NMPOU), PO-related morbidity (e.g. hospital or treatment admissions) and mortality (e.g. overdose deaths) are high in the general population. Most recommendations towards reducing PO-related problems to date have focused on rather narrow and specific areas (e.g. improved PO monitoring, clinical PO use guidelines, detection of patients with PO abuse, tamper-resistant PO formulations). An integrated population health framework for POs-i.e. an evidence-based approach towards largest possible reductions of PO-related harms in the population, as is well established for other psychoactive drug (e.g. alcohol) fields-is currently missing. Recent PO-focused policy initiatives launched in Canada present long lists of recommendations-the feasibility and impact of which on PO-related harms is uncertain-yet also are notably silent on population health-based considerations or approaches. We outline select principal pillars-including general and targeted prevention, and treatment-for a population health framework for PO-related harms and offer suggestions for implementation, with Canada as the principal case study. Given the extensive burden and known population-level determinants of PO-related harms, the development of an evidence-based population health approach to reduce this burden is urgently advised.