Background: oral cancer is the third most common cancer in developing countries. Thymoquinone has a powerful anticancer, antioxidant, and anti-inflammatory properties. Aim: To compare the topical chemopreventive effect of thymoquinone (TQ) versus thymoquinone loaded on gold nanoparticles (GNPs-TQ) on DMBA-induced oral carcinogenesis through histological and immunohistochemical expression of p53. Material & methods: Characterization of the prepared drugs was done through transmission electron microscope, and Ultraviolet-Visible spectroscope. Experimental design: The study was carried out on forty male Syrian golden hamsters, weighing 90-100 grams. Negative control group A (n=10) didn't receive any type of treatment till the end of experiment. Positive control group B (n=10) was painted with DMBA, 3times/week for 14 weeks. Group C (n=10) was daily painted by topical application of TQ for two weeks, and then painted with both TQ and DMBA on alternative days for 14 weeks. Group D (n=10) had been managed as group C but TQ was replaced by GNPsTQ. These groups was examined histologically and immunohistochemically through expression of p53. Results: Proper loading of TQ on GNPs was confirmed. Histopathological evaluation showed superior effect of GNPs-TQ in retardation of carcinogenesis compared to free TQ. Immunohistochemical evaluation revealed significant decrease in P53 expression in the group treated with GNPs-TQ than TQ in comparison with positive control group. Conclusions: GNPs-TQ is a promising chemo-preventive agent of oral cancer through topical application.