ABSTRACT8‐Prenylnaringenin (8‐PN) is one of the most potent phytoestrogens identified to date. Despite its role as an estrogen receptor modulator and its vast therapeutic potential, the effects of this molecule on the brain and behavior of females remain largely unexplored. This study hypothesized that 8‐PN exerts cognitive effects by preventing oxidative damage in the brain and promoting the expression of neurotrophins. Female mice were divided into five groups and received acute treatments with LPS (1 mg/kg), 8‐PN (1 or 2 mg/kg), a combination of LPS and 8‐PN doses, or a combination of vehicle solutions. Recognition memory, spatial memory, and social behavior were assessed using behavioral protocols. Prefrontal cortex and hippocampus samples were collected and analyzed for lipid peroxidation levels using the TBARS assay and for BDNF protein expression using western blot. A single injection of 8‐PN at both doses attenuated the behavioral impairments caused by LPS exposure in recognition memory, spatial memory, and social behavior tasks. 8‐PN at both doses protected the prefrontal cortex and hippocampus against lipid peroxidation, and 8‐PN at 2 mg/kg promoted increased BDNF protein expression in the hippocampus. This study demonstrates that 8‐PN has potential neuroprotective effects in the female brain in vivo and may be a promising drug candidate for preventing cognitive impairments in women.