Oxidative stress plays a central role in the mechanism of gentamicin-induced nephrotoxicity. The antioxidant properties of Cyperus esculentus (CE) have been reported. This study aimed to explore its potential in ameliorating symptoms of nephrotoxicity in a gentamicin-induced model. Tubers of CE were extracted with distilled water. Phytochemical analysis was done using standard protocols. Twenty-five male Wistar albino rats were divided into five groups of five animals each and treated for 8 days: Group I received normal saline, Group II (Gentamicin group)-gentamicin 80 mg/kg + distilled water, Group III-V were administered 80 mg/kg gentamicin +100, 200 and 400 mg/kg CE respectively 1 hour after gentamicin treatment. The rats were anesthetized and blood was collected via cardiac puncture for biochemical analysis. The gentamicin group showed significant increase in serum urea and creatinine levels compared to the control group. Cyperus esculentus resulted in a further elevation of these parameters in a dose-dependent manner. Furthermore, there was a significant increase in serum potassium and a significant decrease in bicarbonate at 400 mg/kg CE. Histological results further buttressed the biochemical findings. In conclusion, oral administration of Cyperus esculentus in gentamicin-induced nephrotoxicity resulted in a further elevation in serum levels of urea, creatinine, and potassium as well as a decrease in serum bicarbonate, and failed to protect against gentamicin-induced nephrotoxicity.