Gamma-glutamyl transpeptidase (GGT) plays a pivotal role in renal glutathione metabolism and redox regulation, and its excessive activation contributes to oxidative stress and tubular injury. Cisplatin (CP) and acetaminophen (Aceta) are well-known nephrotoxic agents primarily inducing renal damage through oxidative mechanisms, whereas amlodipine (Amlo) has been suggested to exert nephroprotective effects. This study aimed to evaluate the protective effect of Amlo against CP- and Aceta-induced nephrotoxicity in rats, with particular emphasis on renal GGT activity and oxidative stress. Fifty-six male albino rats were randomly allocated into seven groups receiving normal saline, CP, Aceta, Amlo, or their respective combinations. Treatments were administered for 14 days, with a single intraperitoneal dose of CP (8 mg/kg) on day 10. Renal GGT activity, oxidative stress markers Reduced Glutathione (GSH), Glutathione Peroxidase (GPx), Catalase (CAT), Superoxide Dismutase (SOD), Malondialdehyde (MDA), and Nitric Oxide (NO), kidney function indices blood urea nitrogen (BUN), serum creatinine (SC), and urea, and histopathological alterations were assessed. Cisplatin markedly elevated renal GGT activity, oxidative stress parameters, and renal dysfunction markers, whereas Aceta induced a milder but significant renal injury. Amlodipine treatment attenuated GGT overactivation, reduced oxidative stress, and improved renal functional and histological integrity, while Aceta co-administration exacerbated CP-induced renal damage. Collectively, these findings indicate that CP induces more pronounced renal GGT activation and oxidative injury than Aceta, and that Amlo confers significant nephroprotection, underscoring the critical role of GGT in drug-induced nephrotoxicity.