Due to extensive application of nanoparticle in industries and medicine, their advantages and disadvantages have been paid attention to. In addition to useful applications, nanoparticles have different effects on body tissue. This study conducted to explore the toxic effect of nickel oxide nanoparticles on oxidative stress system and its damaging effect on the immune system of the rats. In this experimental study, 40 male Wistar rats were randomly divided into two groups. The experimental group received nickel oxide nanoparticles in the form of mixture with water in 25ppm dose for seven consecutive days. The control group received drinking water and food. After 7 days, the serum levels of INF-?, IL-4, MDA, CAT and GPX were measured and the data were analyzed using Independent t-test and SPSS-15 software. Interleukin-4 and interferon-? were significantly increased in the experimental group (25ppm) (P<0.05). MDA was also significantly increased in the experimental group compared with the control group (P<0.05). GPX and CAT were significantly reduced in the experimental group compared with the control group (P<0.05). Nanoparticles of nickel oxide resulted in the creation of free radicals and increased oxidative stress and inflammation in rats.