Introduction: Effective treatment is necessary to minimize the neuronal damage and oxidative stress. Traditional medicines offer potent pharmacological activity with minimal side effects compared to synthetic drugs to treat such chronic disorders. There is no renowned remedy for arrest or rescuing infection or inflammation-induced brain damage. The present study was aimed to evaluate the neuroprotective effect of ethanol extract of Pedalium murex Linn. (EEPM) leaves against lipopolysaccharide (LPS)-induced endotoxemia. Methods: Neurodegeneration was induced in rats with a single intraperitoneal injection of LPS (1 mg/kg). The induced endotoxemia constantly linked with battery of behavioural tests viz., choice reaction time task (CRT), 8-arm radial maze (RAM) and water maze test (WMT). At the end of the study, rats were sacrificed, brain hippocampal region was removed and biochemical parameters were measured. Results: In WMT swimming length (cm) was increased in LPS-treated rats when compared to control animals, the swimming length (EEPM; 400 mg/kg) was found to be significant; in RAM, different doses of EEPM at 100, 200 and 400 mg/kg decreased the number of errors in entry 4.00±0.36, 4.16±0.16and 3.33±2.79 respectively when compared with control animals (2.66± 0.21). EEPM at 400 mg/kg showed significant activity, in CRT apparatus increased incorrect lever pressing was observed in LPS-treated rats when compared to control animals. Incorrect lever pressing was minimized by EEPM at 400 mg/kg (43.5±2.40). Conclusions: Our results showed that EEPM is a hopeful aspirant for hindrance of infection and inflammation induced brain damage by LPS.