Morchella esculenta (L) Pers. is an excellently edible and delicious morel mushroom found growing in the temperate forests. The mycelium of this mushroom is widely used as a flavouring agent. The current investigation was undertaken to explore the protective effect of the aqueous-ethanol extract of cultured mycelium of M. esculenta against cisplatin and gentamicin induced acute renal toxicity in Swiss albino mice. Cisplatin and gentamicin when administered induced a marked renal failure, characterized by a significant increase in serum urea and creatinine concentrations. Treatment with the extract at 250 and 500mg/kg body weight decreased the cisplatin and gentamicin induced increase in serum creatinine and urea levels. Treatment with the extract also restored the depleted antioxidant defense system. The decreased activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) in the kidneys consequent to cisplatin and gentamicin administration was significantly elevated. The enhanced renal antioxidant defense system also prevented the tissue lipid peroxidation. The experimental results suggest that aqueous-ethanol extract of morel mushroom, M. esculenta mycelium protected cisplatin and gentamicin induced nephrotoxicity possibly by enhancing renal antioxidant system. The findings thus suggest the potential therapeutic use of morel mushroom mycelium as a novel nephroprotective agent.