Abstract: Background and Objective: Ginger (Zingiber officinale Rosc.) has been known to exhibit various biological activities such as antioxidant and anti-carcinogenic actions. Nanoparticles of natural compounds believed to have high percentage of flavonoids which present a biological capability for treatment of several diseases including cancer. This study investigated the apoptotic activity as protective action of ginger nanoparticles (GNPs) against the 2,3,7,8-Tetracholorodibenzo-p-dioxin (TCDD) induced initiation of colon cancer in male rats. Materials and Methods: Animals were allocated in nine groups treated with single oral injection/week with TCDD (0.2, 1, 5 and 20 μg kg–1 5 mL–1 corn oil) for one month. GNPs (50 mg kg–1 b.wt.,/everyday) were given to the rats after termination of TCDD injection (at the initiation stage of carcinogenesis) for 2 months. The antioxidant status of treated rats was determined by measuring of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) using standard kits. The expression of several apoptotic related genes Bcl-2, Bax and p53 were analyzed by qRT-PCR. Apoptotic alterations in colon cells were determined morphologically by fluorescent microscope. All obtained data were analyzed using the General Linear Models (GLM) technique. Results: Levels of the antioxidant activity of SOD, CAT, GPx and GST were decreased in TCDD-rats. However, GNPs supplementation significantly enhanced p<0.05 the levels of these antioxidants in TCDD-rats. Expression of Bcl-2, Bax and p53 genes in TCDD-rats was significantly up-regulated. However, GNPs decreased the expression of Bcl-2, Bax and p53 genes in TCDD-GNPs rats. Additionally, the necrotic/apoptotic rate was low in TCDD+GNPs groups, while, high necrotic/apoptotic rate was estimated in TCDD groups. Conclusion: It was concluded that GNPs supplementation inhibits the initiation of colon cancer due to enhancement of the antioxidant activity.