Gentamicin (GM) is a frequently prescribed aminoglycoside antibiotic. Nevertheless, its clinical use is restricted by its nephrotoxic properties. GM-mediated nephrotoxicity elicits chiefly from renal inflammation and oxidative stress. Nicorandil (NR), a synthetic ATP-dependent K channel activator and nitric NO donor, exerts vasodilator, anti-inflammatory, antioxidant, in addition to anti-apoptotic properties. This study was targeted to explore the protecting properties of NR against GM-mediated nephrotoxicity. A daily intraperitoneal dose of 100 mg/kg, of GM given for seven days, induced nephrotoxicity. NR (15 mg/kg), was administered orally every day for 21 days starting 14 days before challenging with GM. Nicorandil repressed the GM-mediated renal injury as verified by the amelioration of the histopathological changes and the considerable reduction in serum BUN, creatinine and KIM-1 levels, in addition to the decline in the relative kidney weight. Notably, NR caused a profound decline in oxidative stress which was verified by the boosted expression of Nrf2 and HO-1 in the renal tissue. Moreover, NR suppressed the inflammation induced by GM; it reduced renal IL-1β, TNF-α and p38 MAPK contents as well as NF-κB p65 expression. Furthermore, NR decreased renal levels of NO and increased eNOS expression. Besides, NR efficiently decreased the expression of Bax and caspase 3 while increased Bcl-2 in renal tissue. Lastly, NR remarkably upregulated the miR-7 and depressed the ER stress marker; CHOP. These findings show that treatment with NR could alleviate GM-mediated nephrotoxicity in rats, highlighting the roles of miR-7 and eNOS in modulating oxidative stress, inflammation in addition to ER stress.