Due to a high rate of oxidative metabolic activity in the brain, intense production of reactive oxygen metabolite occurs, and the subsequent generation of free radicals is implicated in the pathogenesis of traumatic brain injury, epilepsy, and ischemia as well as chronic neurodegenerative diseases. In the present study, protective effects of polyphenol rich ethanolic extract of Boerhaavia diffusa (BDE), a neuroprotective edible medicinal plant against oxidative stress induced by different neurotoxic agents, were evaluated. BDE was tested against quinolinic acid (QA), 3-nitropropionic acid (NPA), sodium nitroprusside (SNP), and Fe (II)/EDTA complex induced oxidative stress in rat brain homogenates. QA, NPA, SNP, and Fe (II)/EDTA treatment caused an increased level of thiobarbituric acid reactive substances (TBARS) in brain homogenates along with a decline in the activities of antioxidant enzymes. BDE treatment significantly decreased the production of TBARS (p < .05) and increased the activities of antioxidant enzymes like catalase and superoxide dismutase along with increased concentration of non-enzymatic antioxidant, reduced glutathione (GSH). Similarly, BDE caused a significant decrease in the lipid peroxidation (LPO) in the cerebral cortex. Inhibitory potential of BDE against deoxyribose degradation (IC50 value 38.91 ± 0.12 μg/ml) shows that BDE can protect hydroxyl radical induced DNA damage in the tissues. Therefore, B. diffusa had high antioxidant potential that could inhibit the oxidative stress induced by different neurotoxic agents in brain. Since many of the neurological disorders are associated with free radical injury, these data may imply that B. diffusa, functioning as an antioxidant agent, may be beneficial for reducing various neurodegenerative complications.