Objective: The present study was undertaken to scientifically evaluate the Nephroprotective activity of the ethanolic extract of fruit pulps of Hylocereus undatus. Method: Cisplatin administration during experimentation effectively induced apoptosis and necrosis, similar to acute renal failure in humans, making it an effective model for nephrotoxicity research. Nephrotoxic rats were treated with the ethanolic extract of Hylocereus undatus, and various renal parameters were evaluated. Results: Treatment with the ethanolic extract significantly elevated the attenuated body weight, urine volume, and creatinine clearance while significantly reducing elevated serum creatinine levels, supporting its Nephroprotective activity. Cisplatin-induced rats showed elevated levels of serum blood urea nitrogen (BUN) and lipid peroxidation parameter malondialdehyde (MDA), which were significantly decreased with treatment, demonstrating nephroprotective activity. The nephrotoxic rats also showed reduced levels of enzymatic antioxidants like superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), and non- enzymatic antioxidants like reduced glutathione (GSH), which were significantly increased with treatment, indicating antioxidant activity due to the flavonoids present in the extract. The ethanolic extract of Hylocereus undatus fruit pulp demonstrated statistically significant nephroprotective activity.