Several receptors have been associated with depression. However, the role of the NOP receptor in depression is not widely recognized yet. It is known that the NOP receptor has wide expression in the nervous system and it has been observed that the activation of this receptor induces inhibitory effects, causing a reduction in the release of neurotransmitters and/or inhibition of neuronal firing, depending on the site (pre-or post-synaptic) in which it is expressed. Thus, this study aims to evaluate the possible behavioral and biochemical effects of the NOP receptor agonist RO65-6570 in mice subjected to the condition of social stress. Methods: Male Swiss mice were employed in this study. To evaluate the depressive behavior in animals, the open field test, social interaction test, and tail suspension test were used. In addition, blood and tissue samples were used to evaluate the oxidative stress in lipids and proteins. Results: The NOP agonist, Ro 65-6570 (1 mg/kg, IP), or the stress of social defeat reduced the exploitation rate in the open field test performed six days after the social defeat protocol. The stress of social defeat or treatment with the NOP agonist also reduced the number of animal surveys in the open field on the penultimate day of the social defeat protocol. The stress of social defeat and/or the NOP agonist increased the immobility time in the tail suspension test performed eight days after the social defeat protocol, as well as reduced the social interaction of the animals on the last day of the social defeat protocol. However, seven days after the end of the protocol, only the drug alone was able to affect the animals' interaction. Additionally, the NOP agonist (1 mg/kg, IP) increased the concentration of carbonylated proteins (carbonyl groups) in the hippocampus. The stress of social defeat and the NOP agonist, together, increased malondialdehyde in the animals' serum and prefrontal cortex, as well as increased the concentration of carbonyl groups in the prefrontal cortex. Finally, the drug alone was able to raise malondialdehyde in the serum. The stress of social defeat and the agonist NOP did not affect the distance traveled in open field test, the animals' weight, defecation, grooming, as well as the concentration of malondialdehyde in the hippocampus. Conclusion: The activation of NOP receptor signaling can facilitate the acquisition of sub-chronic depressive behavior in animals, suggested by some behavioral tests. NOP receptor activation and social defeat stress (together) may be related to lipid peroxidation in the blood and prefrontal cortex of animals, as well as protein oxidation in the prefrontal cortex. The drug by itself may also contribute to serum lipid peroxidation and protein oxidation in the mice's hippocampus. These findings indicate a chronic pro-depressive profile induced by the activation of NOP receptor signaling, sometimes regardless of the presence of the stressor (social defeat protocol).