This study pointed to estimate the possible protective impacts of candesartan and/or epigallocatechin‐3‐gallate (EGCG) against gentamicin‐induced nephrotoxicity. The current work revealed that gentamicin significantly elevated relative kidney weight and the serum level of creatinine and urea. Also, renal level of malondialdehyde was significantly increased with a concurrent decrease in renal glutathione‐S‐transferase and superoxide dismutase activities. Moreover, renal levels of nuclear factor‐kappa B (NF‐κB) and p38 mitogen‐activated protein kinase (p38‐MAPK) were increased together with the elevation of tumor necrosis factor‐alpha and interleukin‐1 beta levels after gentamicin treatment. In addition, caspase‐3 expression was elevated, and histological examination revealed extreme alterations enlightening inflammation, degeneration, and necrosis. Pretreatments with candesartan and/or EGCG attenuated gentamicin‐induced nephrotoxicity. Importantly, the altered expression of p38‐MAPK and NF‐κB may play a significant role in the protective mechanisms exerted by candesartan and EGCG. Coadministration of candesartan and EGCG exhibited more profound response compared with the monotherapy.