Hepatic Encephalopathy (HE) refers to brain function deterioration that occurs as a result of either acute liver failure or chronic liver disease. The main target of the present work was to gain a better understanding of the possible mechanisms by which L-carnitine, α-lipoic acid either individually or in combination can offer their therapeutic action against hepatic encephalopathy in adult male rats. Sixty adult male albino rats were enrolled in the current investigation. They were distributed into six groups: Group (1) control group, Group (2) thioacetamide (TAA) group, Group (3) lactulose-treated group, Group (4) L-carnitine-treated group, Group (5) α-lipoic acid-treated group and Group (6) L-carnitine+α-lipoic acid-treated group. At the end of the experimental period (three months), liver functions test and serum, hepatic as well as brain ammonia levels were quantified. Hepatic and brain oxidant/antioxidant status was evaluated and serum inflammatory markers were quantified. Additionally, histological examination of liver and brain tissue was carried out. The findings of this work showed that the treatment with lactulose, L-carnitine, α-lipoic acid or a combined dose of L-carnitine and α-lipoic acid evoked pronounced improvement in the liver functions accompanied with marked modulation in hepatic and brain oxidant/antioxidant homeostasis in addition to obvious blunting in the inflammatory mediators relative to TAA untreated counterparts. Also, the chosen treatments could restore the structural organization of liver and brain. Conclusively, the outcomes of the present study substantiate the therapeutic ability of L-carnitine, α-lipoic acid or their combination to restore the healing process in the experimental hepatic encephalopathy. The mechanisms behind this effect seem to depend on upregulating hepatic clearance of ammonia, retrieving oxidant/antioxidant homeostasis and downregulating inflammatory status.