<p>Existing pharmacological treatment options for opioid use disorder (OUD) face challenges that limit their efficacy. Accumulating preclinical evidence implicates the orexin/hypocretin system in numerous aspects of OUD development and symptomology: opioid use, opioid-associated cue-driven drug seeking, and opioid withdrawal states that lead to relapse. Further, these studies indicate that selective and dual orexin receptor antagonists (SORAs and DORAs) could constitute promising treatments for OUD and other substance use disorders. Several DORAs have already been approved by the FDA for the treatment of insomnia, making their prospective repurposing potentially straightforward. To this end, recent clinical trials have demonstrated multifaceted efficacy of DORAs for ameliorating opioid craving, withdrawal, and related sleep disturbances in individuals with OUD. Consequently, warranted calls are mounting for the broader use of these agents in the treatment of OUD. This review adopts a translational approach to achieve several aims: (1) to outline the fundamental theories of orexin system function and relate orexinergic dysfunction to the disordered motivation and withdrawal states that characterize OUD; (2) to provide an up-to-date evaluation of preclinical and clinical evidence bases supporting the efficacy of orexin receptor antagonism for the treatment of OUD; (3) to discuss key clinical considerations of repurposing DORAs for OUD treatment, including safety and side effects (i.e., respiratory depression, anhedonia, and risk for abuse); and (4) to highlight the ongoing clinical efforts to determine therapeutic efficacy and safety profiles of DORAs for use in OUD populations.</p>