Objective: Exposure to various toxic metals has become an increasingly recognized source of ill- ness in human and animals, worldwide. Arsenic (As) and its compounds cause adverse health effects in animals and humans. Recently, it has been suggested that the pineal gland may also have antioxidants role due to secretary product other than melatonin. With keeping this view, pre-sent investigation tested effect of buffalo (Bubalus bubalis) pineal proteins (PP) on arsenic-induced oxidative stress in RBCs (Red blood cells) and kidney of rats. Methods: Eighteen adult female Wistar rats were grouped into group-I (Control), group-II (Arsenic control), and group-III (Arsenic + Pineal proteins). Experimental rats were given 100 ppm arsenic (p.o.) for 4 weeks alone or along with pineal proteins at a dose of 100 µg/kg body weight (i.p.). Results: Interestingly, arsenic ex-posure led to the stimulation of kidney catalase (CAT) activity, but inhibition of RBCs CAT activ-ity and significantly (P<0.05) increased the RBCs and kidney lipid peroxidation level (LPO). How-ever, arsenic treatment caused depletion of glu- tathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in kidney tissues. In RBCs, only GR and CAT activity were significantly (P<0.05) declined. These changes were significantly (P<0.05) reversed by PP treatment in arsenic exposed animals. Conclusion: Therefore, present study indicated the significant protecting effect of buf-falo (Bubalus bubalis) PP against arsenic in-duced-oxidative stress through antioxidant de-fense systems in rats.