The present study was conducted to investigate the chemopreventive effects of hydro-ethanolic extract ofEuphorbia neriifolia (EN) on N-nitrosodiethylamine (DENA) induced renal cancer in male Swiss albino mice.Animals were pretreated with EN extract (150 and 400 mg/kg body weight; p.o) and butylated hydroxyanisole(BHA) as a standard (0.5% and 1% BHA p.o) both for two week prior to the administration of single dose ofDENA (50 mg/kg body weight; p.o). Various in vivo antioxidant biochemical parameters like lipid peroxidation(LPO), superoxide dismutase (SOD), and catalase (CAT) were evaluated to determine the reno-protective andantioxidant activity of EN. DENA increased oxidative stress through increase in LPO and decrease in antioxidantenzymes (SOD, and CAT). The EN extract significantly restored the antioxidant enzyme level in the kidneyand exhibited significant dose dependant protective effect against DENA induced nephrotoxicity, which can bemainly attributed to the antioxidant property of the extract. This study rationalized the ethno-medicinal use ofEN for protection against renal cancer.