Background and Aim : Hepatic encephalopathy (HE) is a serious neuropsychiatric syndrome due to hepatic failure. Berberine, an isoquinoline alkaloid isolated from Rhizoma coptidis with antioxidative activity and preserve cell viability induced HE in rats. The aim of current study was to investigate the effect of berberine on cognitive, and brain tissue oxidative stress in adult male rats with thioacetamide (TAA)- induced HE.Methods : 48 adult male Wistar rats (200–250 g ), divided randomly into 6 groups (n=8): Control; received normal saline containing DMSO (2 mL/kg/day, i.p.). HE; received TAA (200 mg/kg/day, i.p.). HE +Ber10; HE rats received berberine (10 mg/kg, i.p.). HE +Ber30; HE rats received berberine (60 mg/kg, i.p.). HE +Ber60; HE rats received berberine (60 mg/kg, i.p.). MK801+HE; HE rats received MK-801 (2 mg/kg/day, i.p.). Berberine and MK-801 were administrated after HE induction at seven alternative days for consecutive 14 days. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), passive avoidance memory in shuttle box and brain tissue oxidative stress were measured. Data presented as Mean SEM and analyzed with ANOVA fallowed by Tukey’s post hoc test. P<0.05 assigned as significant difference.Results : The BBB permeability, brain edema, liver enzymes (ALT and STL), serm total bilirubine, and MDA were increased significantly in HE group versus control (p<0.001). Berberine reversed them dose dependenty (p<0.001). STL and the GPx activity in brain tissue were decrease in HE group versus to control (p<0.001). Berberine could improve them significantly dose dependently (p<0.001). MK-801 through block the NMDA receptors had suppressive effect opposite the TAA to induce HE.Conclusion : In the current study, we showed the beneficial effects of berberine on biochemical and behavioral alterations in HE induced by TAA. Therefore, our data indicate that berberine might be a promising therapeutic agent for HE adverse effects.