We have studied the ability of quercetin (a bioflavonoid) in tackling oxidative stress to alleviate the symptoms during ammonium chloride-induced hyperammonemia. Hyperammonemia was induced by the treatment of ammonium chloride (AC) 100 mg/kg b.w for 56 days. Hyperammonemic rats exhibited reduced urea (in plasma) and increased ammonia (in blood), uric acid (in plasma), creatinine (in serum), oxidative stress markers (thiobarbituric acid reactive substances (TBARS) and hydroperoxides (HP) and decreased levels of antioxidants (enzymatic and non-enzymatic) superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH) in plasma and tissues (liver and brain) vitamins E and C (in plasma)). The expression of liver inflammatory markers such as, interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear transcription factor-κB (NF-κB) (by western blotting) were investigated. Histological damages (in liver, brain and kidney) were observed under hyperammonemia and the administration of quercetin (1) normalized the histopathological alterations, (2) reduced the levels of TBARS and HP, (3) elevated the antioxidants (SOD, CAT, GPx, GSH, vitamins E and C), (4) declined the activities of liver marker enzymes (AST, ALT and ALP) and (5) down regulated the expression of IL-6, iNOS and NF-κB. Our results suggest that quercetin might exert defense to AC-induced hyperammonemic rats to tackle (1) oxidative stress and (2) inflammation owing to its antioxidant, anti-inflammatory and cytoprotective effects.