Background and Purpose: Opioid use disorder (OUD) is a major public health issue. Medications like buprenorphine, methadone, and naltrexone show variable efficacy in reducing opioid craving and use in humans. However, it is unclear if similar individual differences exist in animal models. This study investigated how sex and addiction severity impact these medications’ efficacy in genetically diverse rats. Experimental Approach: Over 500 heterogeneous stock rats underwent intermittent, extended oxycodone self-administration to establish dependence and escalation of intake. Acute effects of single doses of buprenorphine (0.5 mg/kg), methadone (3 mg/kg), and naltrexone (3 mg/kg) on the motivation of oxycodone self-administration were assessed using a progressive ratio schedule. Key Results: Naltrexone and buprenorphine significantly reduced oxycodone self-administration motivation. Naltrexone was effective in both sexes, while buprenorphine only reduced responses in males. Methadone showed no significant reduction across groups, though some rats with moderate to severe addiction-like behaviors displayed reduced responses. Naltrexone’s efficacy was independent of addiction severity, while buprenorphine was more effective in rats with moderate to severe addiction-like behaviors. Conclusions and Implications: This study demonstrates that, genetically diverse rats, like humans, show individual differences in OUD medication efficacy. Addiction severity influenced sensitivity to certain medications, emphasizing the need to consider individual differences in studying OUD’s neurobiological mechanisms and treatments. This study used single doses in an acute pretreatment paradigm; dose-response relationships and chronic treatment effects require further exploration.