Objective: To explore the protective role of Glinus lotoides ethanolic extract in a depression model through modulating oxidant/antioxidant enzyme system and inflammatory status. Methods: Phytochemical constituents of Glinus lotoides ethanolic extract were evaluated qualitatively and quantitatively along with HPLC. Rats were divided into six groups. The normal control and the intoxicated groups received normal saline, and the standard group received imipramine, while the remaining groups received 100, 300, and 500 mg/kg Glinus lotoides ethanolic extract. All groups received treatments for 14 d. Lipopolysaccharides (LPS) were then administered i.p. (0.83 mg/kg) to all groups except the normal control group. After 24 h, anxiety and depression-like behaviors were evaluated by performing behavioral analysis (open field, tail suspension, forced swim, sucrose preference test), and determining total oxidant status, total antioxidant capacity, catalase, and biochemical parameters [malondialdehyde, glutathione, superoxide dismutase, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6]. Results: Phytochemical studies confirmed the presence of phenols and flavonoids and HPLC analysis showed the presence of gallic acid, quercetin, chlorogenic, and caffeic acid. Total oxidant status was significantly decreased, while total antioxidant capacity was significantly increased in the Glinus lotoides ethanolic extract treated groups. Moreover, Glinus lotoides ethanolic extract diminished malondialdehyde, IL-6, and TNF-alpha levels, while increasing superoxide dismutase, catalase, and glutathione activities. Conclusions: Glinus lotoides ethanolic crude extract shows significant antidepressant activity by modulating oxidative and biochemical parameters that supports its folkloric use in traditional systems of medicine.