Agomelatine (AGOM) as an antidepressant acts both as a melatonin-receptor agonist and a selective serotonin-receptor antagonist. As a potent melatonin derived antioxidant, AGOM might modulate depression-induced lipid peroxidation and pro-inflammatory cytokines in brain, kidney and liver. The present study explores whether AGOM protects against experimental depression-induced brain, kidney and liver oxidative stress, and plasma cytokine production in rats with chronic mild stress (CMS)-induced depression. Thirty-six rats were divided into four groups. The first group was used as an untreated control. The second group received AGOM for 4 weeks. The third group was exposed to chronic mild stress (CMS) of 4 weeks for induction depression. The fourth group received 40 mg/kg AGOM and CMS for 4 weeks. Liver and kidney lipid peroxidation levels were high in the CMS group although they were low in AGOM treatments. AGOM and AGOM + CMS treatments increased the lowered glutathione peroxidase activity and reduced glutathione levels in brain, kidney and liver of CMS group. beta-carotene, vitamin A and vitamin E concentrations in the brain, kidney and liver of the four groups were not changed by CMS and AGOM treatments. However, plasma TNF-alpha, interleukin (IL)-1 beta, and IL-4 levels were high in the CMS and AGOM group and their levels were further increased by the AGOM + CMS treatment. In conclusions, AGOM induced protective effects against experimental depression-induced brain, kidney, and liver oxidative injuries through regulation of the glutathione concentrations and glutathione peroxidase activity. However, plasma cytokine productions were increased by the AGOM treatment.