The gravity of the impact of renal failure on human health is well known and as there is no specific pharmacotherapy for renal failure, the current study was undertaken to evaluate the effect of root extract of Azima tetracantha, an ancient medicinal plant used in Siddha and Ayurvedhic systems of medicine. The experiment was done in glycerol-induced acute renal failure in Wistar albino rats. Thirty rats were divided into five groups. Group 1 was given normal saline (10 ml/kg) per oral, group 2 with single dose of hypertonic glycerol (8 ml/kg) by intramuscular injection into the hind limbs, group 3 with glycerol and ethanolic extract of A. tetracantha root (ATR) 250 mg/kg, group 4, glycerol and ATR 500 mg/kg and group 5, 500 mg/kg ATR. Extract was given orally 60 min prior to glycerol injection. 24 h urine output, serum creatinine, blood urea nitrogen, total proteins and albumin were measured for all the groups. Kidneys were examined for histopathological changes. The antioxidant activity of the extract was tested in vitro and in vivo. Rats treated with ATR showed significant improvement in biochemical parameters and histopathological changes compared to glycerol treated group. The protective effect was highly significant at 500 mg/kg. Both in vitro and in vivo assays showed significant antioxidant activity. The in vitro activity was comparable to vitamin-C. The ethanolic extract of ATR has nephroprotective effect in glycerol-induced acute renal failure and the mechanism of action could be the antioxidant effect.