<p>Cisplatin is a highly effective chemotherapeutic agent used to treat various solid tumors; however, its clinical utility is limited by dose-dependent nephrotoxicity. Perampanel, an AMPA-receptor antagonist FDA-approved anti-seizure drug, has recently shown inhibitory effects on oxidative stress and inflammasome-mediated pyroptosis in neurological damage models. The current work examined the possible renoprotective benefits and clarified the underlying molecular signaling modified by perampanel in a cisplatin-renal injury model. Male Wistar rats were used to investigate the effect of perampanel (1 &amp; 2 mg/kg/day, for 14 days) against renal injury induced by cisplatin (10 mg/kg, on the 9th day), followed by morphological, histopathological, immunohistochemical (IHC), and biochemical estimations. The administration of perampanel to cisplatin-injected rats maintained the kidney-to-body weight ratio and renal function in a dose-dependent manner. Besides, there was a great improvement in the histological features compared to the cisplatin group. IHC analysis revealed the efficient inhibitory impact of perampanel against cisplatin-induced upregulation of NF-κB p65, NLRP3, and caspase-1 expressions. Consequently, the activation of interleukin (IL)-18 and -1β inflammatory cytokines was interrupted, and their renal levels were not elevated. Eventually, the pyroptosis effector protein, gasdermin D (GSDMD), upregulation was impeded. Inflammasome inhibition by perampanel was accompanied by downregulation of the promoter signaling NF-κB p65/TNF-α, enhancement of sirtuin 3/FOXO3 antioxidant signaling alongside upregulated Nrf-2 mRNA expression and antioxidant proteins, as well as maintained balance of Bax/Bcl-2; pro-/anti-apoptotic; genes<i>.</i> Collectively, perampanel could attenuate cisplatin-induced renal injury through its inhibitory influence on NF-κB p65/TNF-α and NLRP3-mediated pyroptosis, in addition to enhancement of antioxidant defense and controlling apoptosis.</p>