BACKGROUND Euphorbia hirta (L.) (Euphorbiaceae) is a very popular herb amongst practitioners of traditional medicine and used in the treatment of female disorders, respiratory ailments, tumors, jaundice, digestive problems, wounds, etc. We aimed to evaluate the protective effect of E. hirta against nitrobenzene-induced nephrotoxicity in albino rats. METHODS The nephroprotective activity of the ethanol extract of E. hirta (400 mg/kg body weight) was studied in nitrobenzene-induced albino rats (1000 mg/kg body weight). The activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and the levels of reduced glutathione (GSH), total thiols and vitamin C in the kidney tissues were determined. Histopathologic investigation was performed in the kidney tissue samples. RESULTS Nitrobenzene administration significantly (P < 0.01) enhanced the lipid peroxidation and significantly (P < 0.05) depleted the levels of SOD, CAT, GPx, GST, GSH, total thiols and vitamin C. Treatment with the ethanol extract of E. hirta significantly normalized the antioxidant levels. The nephroprotective activity was also supported by histopathologic studies of kidney tissue. CONCLUSIONS The results indicate that the ethanol extract of E. hirta ameliorates renal dysfunction and could be used as an effective protector against nitrobenzene-induced nephrotoxicity, primarily through its antioxidant capacity.