Background: The possible ameliorative effects of the methanolic extract of the rind of Citrullus lanatus on some erythrocyte parameters, serum superoxide dismutase and malonaldehyde concentrations were investigated following phenylhydrazine administration using wistar rats as models. Methods: Adult male Wistar rats were randomly divided into 5 groups: Group 1 were untreated controls; Group 2 received only phenylhydrazine: negative controls; Group 3 received phenylhydrazine +100 mg/kg of extract; Group 4 received phenylhydrazine +500 mg/kg of extract; Group 5 received phenylhydrazine + 0.23 ml/kg of Bioferon®: positive controls. In all groups, phenylhydrazine was administered via the intraperitoneal route at a dose of 40 mg/kg body weight on day 0, with two additional doses given on day 1 of the experiment; the extract of the rind of Citrullus lanatus and Bioferon were both administered orally for 14 days. On day 15, the rats were placed under chloroform anesthesia and blood collected by direct cardiac puncture. Red blood cell counts, hemoglobin concentration and haematocrit were determined using automated methods; serum superoxide dismutase and malondialdehyde concentrations were determined by standard methods. Results: Amongst Group 2 rats, administration of phenylhydrazine significantly reduced all erythrocyte parameters and superoxide dismutase concentrations but significantly increased malondialdehyde concentrations compared to Group 1 rats (p<0.05). However, administration of the extract and Bioferon significantly increased values of all erythrocyte parameters and superoxide dismutase concentration and significantly reduced malondialdehyde concentration amongst both Groups 4 and 5 rats respectively compared to Group 2 rats. Only the values of superoxide dismutase were significantly elevated amongst Group 3 rats; suggesting a possible dose dependence of the effects of the extract. Conclusion: Results suggest a possible ameliorative potential of the rind of Citrullus lanatus on the erythrocyte parameters and indices of oxidative stress and lipid peroxidation following phenylhydrazine administration. The observed effects of the rind of Citrullus lanatus could possibly result from summation of the effects of both its antioxidant and nutritional constituents. Our findings are essentially preliminary and could benefit from further investigations.