The present study aimed to assess the antioxidative, anti-in ammatory, antiapoptotic, and antidepression impacts of Moringa oleifera Lam. leaf ethanolic extract (MOLE) in the hippocampus and cerebral cortex of CCl 4 -induced mouse model of hepatic encephalopathy. High-performance liquid chromatography was used to detect marker compounds; rutin and β-sitosterol. Animals were divided into four groups; vehicle group, CCl 4 treated group, MOLE treated group, and (CCl 4 + MOLE) group treated with MOLE for 14 days before CCl 4 -induced neurotoxicity. MOLE decreased alanine aminotransferase, aspartate aminotransferase, corticosterone, and ammonia levels in serum and improved the antioxidant status of CCl 4 treated mice in the hippocampus and cerebral cortex. It reduced the expression of toll-like receptor (TLR)4, TLR2, myeloid differentiation primary response 88 (MYD88), and nuclear factor-kappa B (NF-κB) genes and the protein levels of the pro-inflammatory cytokines. MOLE also attenuated apoptosis, as revealed by the reduced expression of caspase3, and prevented histological deterioration. Furthermore, MOLE attenuated CCl 4 -induced anxiety and depression-like behavioral changes. Collectively, MOLE modulates neuroin ammation, oxidative stress, TLR4/2-MyD88/NF-κB signaling, and apoptosis in the hippocampus and cerebral cortex of the hepatic encephalopathy experimental model.