Severe Acute Liver Failure (SALF) is characterized by sudden dysfunction of liver cells in previously healthy persons without known underlying liver disease. Effective therapeutic approaches are necessary in an attempt to minimize the damage resulting from liver failure. Glutamine is considered to be an amino acid that plays many essential metabolic functions. This study was designed to evaluate the action of glutamine in protecting against cellular disturbances resulting from Thioacetamide (TAA)-induced SALF in rats. Two doses of thioacetamide (400 mg/kg) and 3 doses of glutamine (25 mg/kg) (ip) were administered. The experiment lasted 48 hours. Glutamine reduced blood levels of AST and ALT in TAA-treated rats. Histological evaluation indicated that glutamine acted in tissue protection by reducing the inflammatory infiltrate, ballooning and centrilobular necrosis induced by SALF, consequently restoring the hepatic parenchyma. Glutamine increased total protein levels and decreased carbonylated protein levels in the liver of SALF animals. Glutamine also acted by modulating HSF-1 and heat shock proteins expression, as well as by decreasing the expression of proteins involved in endoplasmic reticulum stress (GRP78, ATF6 and CHOP), and modifying the expression of apoptosis-related (Bcl -2, Bax and caspase 3) and autophagy-related (mTOR, Beclin1 and LC3α/β) proteins. These effects related to changes in PI3K, Akt and FOXO3a expression. Data obtained support a potential hepatoprotective role of glutamine in SALF.