Cisplatin has demonstrated high antitumor efficacy. However, nephrotoxicity is a dose-limiting factor in its clinical use. The present study was designed to investigate the protective effect of rutin and low dose of irradiation (LDR) on cisplatin-induced nephrotoxicity in rats. Rats received rutin (200mg/kg/day, p.o) for 10 consecutive days and subjected to LDR (0.5Gy) 1day prior to cisplatin. Intraperitoneal administration of single dose of cisplatin (7.5mg/kg) was used to induce nephrotoxicity. Data showed that cisplatin caused elevation in serum creatinine and urea, disturbance in blood count, elevation in gene expression of tumor necrosis factor alpha, nuclear factor kappa B, interleukin-1β, caspase-3, mitochondrial cytochrome C and apoptosis-inducing factor in renal tissue. Moreover, it caused elevation in renal malondialdehyde accompanied by reduction in glutathione content. These effects were confirmed by histopathological examination. It was observed that LDR and rutin ameliorated the studied parameters. In conclusion, LDR could be considered as a novel approach for prophylaxis of cisplatin induced renal damage, also it augmented the nephroprotective effect of rutin via modulating the expression of inflammatory, oxidative stress and apoptotic mediators as well as histological changes in rats kidneys and hence might be valuable in improving the therapeutic index of cisplatin.