The present research aimed to evaluate the hepato/neuroprotective effects of Rutin and Resveratrol as natural antioxidants on brain and liver tissues of experimental rats exposed to acute liver failure induced by i.p. administration of Thioacetamide (TAA), Through evaluation of plasma and brain Ammonia, serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP) and Gamma Glutamyl-Transferase (γ-GT), Albumin, Total Protein, Total Bilirubin, Urea and Uric acid. Levels of reduced glutathione (GSH) and activities of Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx), were determined in the liver and brain tissues. Extent of oxidative stress was also assessed by hepatic and brain lipid peroxides (MDA), in addition to brain nitric oxide (NO) and Monoamine oxidase (MAO). Thioacetamide induced a significant increase in 1) ALT, AST, ALP, γ-GT, Albumin; Total Protein, Total Bilirubin, Urea and Uric acid Levels in serum, 2) plasma and brain ammonia level 3) brain NO level, 4) liver and brain MDA. Also marked depletion in liver and brain GSH, CAT, SOD, GPx and brain MAO were observed after TAA intoxication. Rutin and Resveratrol Pretreatment was able to mitigate hepatic and brain damage induced by TAA and showed pronounced curative effect against lipid peroxidation and deviated serum enzymatic variables as well as maintained glutathione status and antioxidant enzymes toward control levels. Pretreatment of rutin and resveratrol was highly effective and protective against TAA induced hepatic encephalopathy. The results of the present study suggest that rutin and resveratrol have potential to exert curative effects against liver injury.