Background: Oral canceris one ofthe most prevalent cancers. Thymoquinone (TQ) has a potential therapeutic activity against cancer cells. Aim: This study aimed to compare the effect of TQ and TQ loaded on gold nanoparticles (GNPs) as systemic therapeutic agents through intra-peritoneal injection for 3&6 weeks after painting with DMBA (3 times/week for 14w). Material and Methods: This study was carried out on ninety male Syrian golden hamsters (n=90), its age ranged from 6 to 7 weeks, weighting 90-110 gm, purchased from Theodore Blhars Research Institute, Cairo, Egypt. Characterization of GNPs was achieved through using Ultraviolet-Visible spectroscope and transmission electron microscope (TEM). Analysis for total white blood cells (WBCs) & lymphocytes count and lymphocytes % was done. To ensure the drugs safety, liver and kidney toxicity enzymes were measured. Results: Formation of spherical and well dispersed GNPs (27nm). There was marked increase in WBCs (13.8), lymphocyte count (8.2) and liver enzymes (99.6-104.4) after DMBA painting. These markers were reduced obviously after using of GNPs-TQ for 6w to 6.1, 5.4, 56.7, and 57.5 respectively. Histopathological evaluation showed regression of carcinogenesis and regeneration of striated muscle layers when treated with GNPs-TQ. Conclusions: GNPs-TQ is considered a promising chemo-therapeutic agent in treating carcinoma, without toxic effect on liver and kidney enzymes