<p><b>Background</b>: Abuse of prescription opioids is a serious problem in North America.</p> <p><b>Aims</b>: The aim of this study was to conduct a systematic review of peer-reviewed and grey literature to examine existing strategies aimed at improving the appropriate use of prescription opioids and/or reducing the misuse, abuse, and diversion of these drugs.</p> <p><b>Methods</b>: The following electronic databases were searched to September 2015 without language restrictions: MEDLINE, EMBASE, PsycINFO, and CINAHL; the grey literature was searched to May 2014. Reference lists of retrieved papers were also searched. Studies were eligible if a strategy was implemented and its impact on at least one of the primary outcomes of interest (appropriate prescription opioid use; misuse, abuse, opioid use disorder, diversion; overdose) was measured. Standardized, prepiloted forms were used for relevance screening, quality appraisal, and data extraction.</p> <p><b>Results</b>: A total of 65 studies that assessed 66 distinct strategies were identified. Due to the heterogeneity of the strategies, a qualitative synthesis was conducted. Many studies combined more than one type of strategy and measured various types of outcomes. The strategies with most promising results involved education, clinical practices, collaborations, prescription monitoring programs, public campaigns, opioid substitution programs, and naloxone distribution. We also found strategies that had some unintended consequences after implementation.</p> <p><b>Conclusions</b>: Our review identified successful strategies that have been implemented and evaluated in various jurisdictions. There is a need to replicate and disseminate these strategies where the problem of prescription opioid misuse and abuse has taken a toll on society.</p