The objective of the current study was to investigate the protective effects of hesperidin against oxidative stress, altered cytokines levels and histological changes in rats induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rats were divided randomly into four equal groups (Control, TCDD, hesperidin and TCDD+hesperidin). TCDD and hesperidin were given by gavage, dissolved in corn oil at doses of 2 mu/kg/week and 50 mg/kg/day respectively. The blood and tissue samples were taken from all rats on the 60th day, to be analyzed for the determination of oxidative stress, histological changes and cytokine levels. The results indicated that hesperidin prevented oxidative damage caused by TCDD via decrease lipid peroxidation and increased antioxidant defense systems. It also reversed the histological damage induced by TCDD. Although, TCDD led to a significant increase in TNF-alpha and IL-1 beta levels, hesperidin treatment was able to normalize these values in rats. In conclusion, it was shown that TCDD caused adverse effects as regards cytokine levels, histological alterations and oxidative stress in rats. However, hesperidin treatment mitigated these toxic effects. These results suggest that hesperidin could play a protective role against TCDD toxicity.