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Background: Rice (<i>Oryza sativa</i> L.) is the main food source for more than half of humankind. Rice is rich in phytochemicals and antioxidants with several biological activities; among these compounds, the presence of &#947;-oryzanol is noteworthy. The present study aims to explore the effects of &#947;-oryzanol on cognitive performance in a mouse model of neuroinflammation and cognitive alterations. Methods: Mice received 100 mg/kg &#947;-oryzanol (ORY) or vehicle once daily for 21 consecutive days and were then exposed to an inflammatory stimulus elicited by lipopolysaccharide (LPS). A novel object recognition test and mRNA expression of antioxidant and neuroinflammatory markers in the hippocampus were evaluated. Results: ORY treatment was able to improve cognitive performance during the neuroinflammatory response. Furthermore, phase II antioxidant enzymes such as heme oxygenase-1 (HO-1) and NADPH-dehydrogenase-quinone-1 (NQO1) were upregulated in the hippocampi of ORY and ORY+LPS mice. Lastly, &#947;-oryzanol showed a strong anti-inflammatory action by downregulating inflammatory genes after LPS treatment. Conclusion: These results suggest that chronic consumption of &#947;-oryzanol can revert the LPS-induced cognitive and memory impairments by promoting hippocampal antioxidant and anti-inflammatory molecular responses.