<p>The present study tested for the first time the safety of sulfasalazine at dose of 100 mg/kg on renal function, in addition to study its possible renal effects on cisplatin-induced nephrotoxicity in rat model. Furthermore, it aimed to investigate the modulatory effect of sulfasalazine on NF-κB. Forty-eight male Sprague–Dawley rats were divided into four groups: negative control (given a daily oral dose of normal saline), cisplatin (given a single dose of Cisplatin, 6 mg/kg, i.p.; nephrotoxicity model), sulfasalazine (given a daily dose of SFZ, 100 mg/kg, orally via gavage; control model), and Cis + SFZ (given 100 mg/kg sulfasalazine, orally, 5 days before and 14 days after the cisplatin dose). Nephrotoxicity was evaluated 96 h and 14 days following cisplatin administration. Cisplatin nephrotoxicity was evidenced by significant rises in renal indices of functional, inflammatory, fibrotic, apoptotic and histological profiles. It also up-regulated miR-375 and miR-132-3p expression. Decreased p-AMPK, SIRT-1, HNF-1B and total antioxidant levels in kidney homogenates were also observed at 96 h following cisplatin injection. Sulfasalazine alone didn’t show any change in renal parameters compared to the saline-treated group but counteracted cisplatin-induced nephrotoxic changes. The obtained results revealed that sulfasalazine at the dose of 100 mg/kg offered a renoprotective effects against cisplatin-induced nephrotoxicity which could be attributed to its inhibition of NF-κB-p65 via downstream attenuation of inflammatory, apoptotic and fibrotic pathway. This inhibitory effect of sulfasalazine on NF-κB-p65 could be at least in part attributed to its upstream modulation of p-AMPK, SIRT1, miRNA-132-3p and miR-375.</p> Graphical abstract <p></p>