Background: Citrullus lanatus seeds are known to be highly nutritious, and rich sources of phenolic compounds. They are usually milled into flour and used for making sauces, snacks, and cooking oil. Aim:To investigate the in vivo antioxidant capacity and effect of sub-chronic doses of methanol extract of C. lanatus seed on renal function.Methods: Adult male Wistar rats (n = 35) weighing 130 to 170g (mean weight = 150 ± 20g) were randomly assigned to seven groups of five rats each: normal control, Tween 80 control, and five treatment groups. Rats in the treatment groups received graded doses of the extract (10 -5000 mg/kg body weight, bwt) orally for 35 days. Indices of renal function and oxidative stress were assayed. Results:The absolute and relative weights of kidneys of rats in each group were not significantly affected by extract treatment (p > 0.05). There were significant increases in the final body weight and percentage weight increase in the treatment groups, relative to normal control group (p < 0.05). Methanol extract of C. lanatus seed did not significantly alter the levels of electrolytes, creatinine, malondialdehyde (MDA) and reduced glutathione (GSH), as well as activity of Superoxide Dismutase (SOD) among the groups (p > 0.05). Moreover, Tween 80 significantly increased the levels of bicarbonate ion, urea and urea/creatinine ratio (p < 0.05). Conclusion:These results show that methanol extract of Citrullus lanatus seed is not nephrotoxic and possesses high antioxidant activity in vivo.