The aim of the present study was to investigate the impact of arginine (ARG), a nitric oxide (NO) precursor, on thioacetamide (TAA)-induced hepatic encephalopathy (HE) in rats by injection of TAA (100 mg/kg, i.p) three times per week for six consecutive weeks. TAA-injected rats were administered ARG (100 mg/kg; p.o.) concurrently with TAA for the six consecutive weeks. Blood samples were withdrawn, and rats were sacrificed; liver and brain tissues were isolated. Results of the present study demonstrated that ARG administration to TAA-injected rats revealed a restoration in the serum and brain ammonia levels as well as serum aspartate transaminase, alanine transaminase, and alkaline phosphatase and total bilirubin levels as well as behavioral alterations evidenced by restoration in locomotor activity, motor skill performance, and memory impairment. ARG showed also improvement in the hepatic and neuro-biochemical values, pro-inflammatory cytokines, and oxidative stress biomarkers. All these results were confirmed by histopathological evaluation as well as ultrastructural imaging of the cerebellum using a transmission electron microscope. Furthermore, treatment with ARG could ameliorate the immunological reactivity of nuclear factor erythroid-2-related factor 2 (Nrf2) and cleaved caspase-3 proteins in the cerebellum and hepatic tissues. From all the previous results, it can be fulfilled that ARG showed a beneficial role in modulating the adverse complications associated with TAA-induced HE in rats via reducing hyperammonemia and downregulating nuclear factor kappa B (NF-κB)-mediated apoptosis.