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Social defeat stress (SDS) due to changes in biochemical functions has been implicated in the pathogenesis of affective and cognitive disorders. Employing pharmacological approach with adaptogens in the management and treatment of psychosocial stress is increasingly receiving scientific attention. In this study, we investigated the neuroprotective effect of rutin, a bioflavonoid with neuroprotective and anti-inflammatory functions on neurobehavioral and neuro-biochemical changes in mice exposed to SDS. Groups of mice named the intruder mice received normal saline (10 mL/kg), rutin (5, 10, and 20 mg/kg, i.p.), and ginseng (50 mg/kg, i.p.) daily for 14 days, and then followed by 10 min daily SDS (physical/psychological) exposures to aggressor mice from days 7-14. Investigations consisting of neurobehavioral (locomotion, memory, anxiety, and depression) phenotypes, neuro-biochemical (oxidative, nitrergic, cholinergic, and pro-inflammatory cytokines) levels in discrete brain regions, and hypothalamic-pituitary-adrenal (HPA) axis consisting adrenal weight, corticosterone, and glucose concentrations were assessed. Rutin restored the neurobehavioral deficits and reduced the activity of acetylcholinesterase in the brains. Adrenal hypertrophy, increased serum glucose and corticosterone levels were significantly attenuated by rutin. SDS-induced release of tumor necrosis factor-alpha and interleukin-6 in the striatum, prefrontal cortex, and hippocampus were also suppressed by rutin in a brain-region-dependent manner. Moreover, SDS-induced oxidative stress characterized by low antioxidants (glutathione, superoxide-dismutase, catalase) and lipid peroxidation and nitrergic stress were reversed by rutin in discrete brain regions. Collectively, our data suggest that rutin possesses an adoptogenic potential in mice exposed to SDS via normalization of HPA, oxidative/nitrergic, and neuroinflammatory inhibitions. Thus, may be adopted in the management of neuropsychiatric syndrome due to psychosocial stress.