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Opioid use disorder (OUD) has reached epidemic proportions, with many countries facing high levels of opioid use and related fatalities. Although currently prescribed medications for OUD are considered lifesaving, they inadequately address negative affect and cognitive impairment, resulting in high relapse rates to nonmedical opioid use even years after drug cessation (protracted abstinence). Evidence supports the notion that ketamine, an anesthetic and rapid-acting antidepressant drug, holds promise as a candidate for OUD treatment, including the management of acute withdrawal somatic symptoms, negative affect during protracted opioid abstinence, and prevention of retaking nonmedical opioids. In this review, we comprehensively discuss preclinical and clinical research that has evaluated ketamine and its metabolites as potential novel therapeutic strategies for treating OUD. Furthermore, we examine evidence that supports the relevance of the molecular targets of ketamine and its metabolites in relation to their potential effects and therapeutic outcomes in OUD. Overall, existing evidence demonstrates that ketamine and its metabolites can effectively modulate pathophysiological processes affected in OUD, suggesting a promising therapeutic role in the treatment of OUD and the prevention of return to opioid use during abstinence.