The use of prescription opioid analgesics, particularly oxycodone, has dramatically increased, and parallels escalated opioid abuse and drug-related deaths worldwide. Understanding the molecular mechanisms underlying the development of opioid dependence and expanding treatment options to counter prescription opioid abuse has become a critical public health matter. In the present study, we first evaluated the reinforcing effects of oxycodone in a rat model of self-administration and then explored the potential utility of two novel high affinity dopamine D3 receptor (D3R) antagonists/partial agonists, CAB2-015 and BAK4-54, for treatment of prescription opioid abuse and dependence. We found that rats acquired oxycodone self-administration rapidly within a range of unit doses that was similar to that for heroin, confirming that oxycodone has significant abuse potential. Strikingly, pretreatment with either CAB2-015 or BAK4-54 (0.4–10 mg/kg, i.p.) dose-dependently decreased oxycodone self-administration, and shifted the oxycodone dose-response curve downward. Repeated pretreatment with CAB2-015 or BAK4-54 (0.4–4 mg/kg) facilitated extinction and inhibited oxycodone-induced reinstatement of drug-seeking behavior. In addition, pretreatment with CAB2-015 or BAK4-54 (4–10 mg/kg) also dose-dependently decreased oxycodone-enhanced locomotor activity, but only CAB2-015 decreased oral sucrose self-administration. These data suggest that D3R antagonists may be suitable alternatives or adjunctive to opioid-based medications currently used clinically in treating opioid addiction and that the D3R-selective ligands (CAB2-015 or BAK4-54) provide new lead molecules for development.