Xenobiotic-induced oxidative stress is a principal cause of kidney damage. Antioxidants may prevent oxidative stress that leads to kidney damage. Bergenin, a C-glucoside derivative of gallic acid, is abundant in plants of the Mallotus, Bergenia, and Ardisia genera. Bergenin has been reported as an effective antioxidant that can scavenge free radicals and has previously been shown to protect rat and mouse kidneys against oxidative damage, but its nephroprotective impact against xenobiotic-induced renal oxidative damage has not been assessed in vivo. The present study assessed the nephroprotective effects of bergenin on the renal antioxidant system in ethanol, sodium selenite (SS), and tert-butyl hydroperoxide (TBHP) induced renal oxidative stress in mice. Adult male ICR mice were administered ethanol (1.5-2 g/kg/day; peroral, p.o.), SS (4 mg/kg/day; p.o.), or TBHP (18 mg/kg/day; i.p.) in combination with bergenin (10, 50, and 250 mg/kg/day; p.o.) or gallic acid (100 mg/kg/day; p.o.; positive control) for 7 consecutive days. Ethanol, SS, and TBHP suppressed the activity of the main renal antioxidant enzymes, namely superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Furthermore, ethanol, SS, and TBHP depleted renal glutathione stores, which substantially decreased the reduced glutathione (GSH) to oxidized glutathione (GSSG) ratio, and boosted the formation of renal malondialdehyde (MDA). Treatment with bergenin and gallic acid attenuated the renal damage associated with xenobiotic-induced oxidative stress in the mouse kidneys by increasing the activity of the SOD, CAT, and GPx antioxidant enzymes and restoring the glutathione stores, which lead to an extraordinary decline in MDA levels. Thus, bergenin and gallic acid demonstrated a comparable nephroprotective potential that was mediated through the improvement of the renal antioxidant defense machinery. Therefore, bergenin is a promising nephroprotective candidate for xenobiotic-induced oxidative stress.