Cisplatin (Cis) is an extensively prescribed chemotherapeutic agent inducing acute kidney injury (AKI) and nephrotoxicity. This study explored the possible nephroprotective effects of the antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Empa) against Cis-induced endothelial dysfunction and elaborated its underlying protective mechanisms. Empa (5–60 mg/kg, orally) was administered to male rats for 14 days and nephrotoxicity was induced by a single intraperitoneal injection of Cis (5 mg/kg, i.p.) at day 11 of Empa administration. Empa nullified Cis induced rise in plasma urea and creatinine. On isolated perfused kidney, Empa: a) restored phenylephrine (0.41–900 ng) intensified renal vasoconstriction, b) reinstated renovascular responsiveness to endothelium-dependent vasodilation evoked by acetylcholine (0.01–2.43 nmol), c): restored the Emax and EC50 values of ACh dose-response curves, such effects were abolished following coadministration of L -NAME, d) unchanged the vasodilatory effect of sodium nitorprusside (0.001–10 μmoles) after treatment with Cis. alone or combined with L -NAME. Empa decreased renal p-eNOS, p-eNOS/t-NOS ratio and ET-1 levels in western blot analysis and reduced plasma Nox level. Empa ameliorated renal oxidative stress (lowered reduced glutathione and increased malondialdehyde levels), reduced plasma cytokine levels (IL-1β, TNF-α), and plasma apoptotic markers (Bax and caspase 3) induced by Cis. Furthermore, immunohistochemical studies showed that Empa mitigated Cis-induced increase in the renal expression of MAPK _p38 , TGF-β and SMAD3 and histologically, attenuated Cis induced glomerular and endothelial necrosis and dilatation of the renal tubular lumen. Collectively, Empa effectively mitigated endothelial dysfunction and nephrotoxic effects caused by Cis through amending oxidative stress, inflammation, apoptosis and renal fibrosis.