Addiction is a chronic condition that poses a serious public health challenge, particularly highlighted by the global opioid crisis involving drugs such as morphine (MORPH). One of the major obstacles in effective detoxification is the high relapse rate, with many individuals resuming drug use after withdrawal. Pharmacological treatments developed so far have generally shown limited efficacy in addressing substance use disorder. In this context, esketamine (ESK), the S-ketamine isomer, has been used in cases of treatment-resistant recurrent depression and depression with suicide risk. In our study, rats were treated with two doses of ESK every five days (acute - A-ESK) or daily (sub-chronic - SC-ESK) during MORPH-conditioned place preference (CPP) extinction. After 10 days, the animals were re-exposed to MORPH to assess preference reacquisition in the CPP paradigm. Our findings showed that both acute and sub-chronic ESK (A-ESK and SC-ESK) effectively prevented MORPH-CPP reestablishment. To our knowledge, this is the first experimental study to demonstrate the potential of ESK as a promising treatment for opioid abuse disorder. Clinical studies are needed to confirm its efficacy in human rehabilitation centers.