The present study aims to evaluate the antidepressant efficacy of curcumin nanoparticles on rat model of depression induced by reserpine. Rats were divided into control, the rat model of depression induced by daily i.p. injection of reserpine (0.2 mg/kg for 21 days), and the rat model of depression treated daily with the formulated CNPs (20 mg/kg for 7 and 15 days). The behavioral evaluation was assessed for all groups of animals by the forced swim test (FST). Monoamine neurotransmitters were measured in the cortex and hippocampus via fluorescence spectroscopy. The electrophysiological evaluation was carried out by recording and analyzing the electrocorticogram (ECoG) in a group of animals that served as self-control. The chronic administration of reserpine resulted in a significant decrease in the duration of the active phase in the FST; a significant decrease in the cortical and hippocampal levels of serotonin, norepinephrine, and dopamine; a significant increase in spectral power of alpha and delta waves; and a significant decrease in spectral power of theta, beta-1, and beta-2 waves with respect to control values. Administration of CNPs for 7 days has improved the performance of animals in FST indicated by the increase in the duration of the active phase. Additionally, the levels of serotonin and dopamine have been restored; however, the level of norepinephrine has been not completely recovered in both cortex and hippocampus. A significant increase in alpha and beta-2 waves, an increase in theta and beta-1, and a decrease in delta waves have been recorded after 7 days of treatment. Extending treatment with CNPs for 15 days has succeeded in restoring the active phase in FST and monoamine level in the cortex and hippocampus to control like values. In addition, ECoG waves have returned to near control like values. It could be concluded that the formulated nanocurcumin has an effective and potent antidepressant activity that was evidenced by electrical, chemical, and behavioral tests.