Sodium valproate, one of the most widely used antiepileptic drugs, has been noted to induce nephrotoxicity through elevation of oxidative stress. Carvedilol, a non-specific beta-adrenergic blocker, and rosuvastatin, an anti-hyperlipidemic, possess antioxidant characteristics. This study was planned to estimate the promising defensive impacts of Carvedilol and/or rosuvastatin against valproate‐induced nephrotoxicity. It was revealed that sodium valproate (SVP) markedly boosted serum creatinine (SCr) and blood urea nitrogen (BUN). Moreover, glutathione level (GSH) was decreased with a concomitant elevation in renal malondialdehyde level (MDA) and inducible nitric oxide synthase activities (iNOS). After SVP treatment, there were significant elevations in renal tumor necrosis factor‐alpha (TNF-𝛼) and nuclear factor‐kappa B (NF‐κB). Additionally, SVP‐induced suppression of nuclear related factor 2 (Nrf2) pathways. Furthermore, histopathological examination showed prodigious inflammation, necrosis, congestion and degeneration. Coadministration of Carvedilol and/or rosuvastatin mitigated nephrotoxicity induced by SVP. Using the combination of Carvedilol and rosuvastatin presented additional intense renal protective effect when compared with each alone.