This study aimed to compare the effects of Thymoquinone (TQ), Epigallocatechin gallate (EGCG) and Curcumin (CUR) on the inhibition of progression of oral premalignant lesions to invasive carcinoma through detection of PCNA and Caspase 3 expression. Thirty Syrian golden hamsters were divided into 5 groups (n=6). G.A: no treatment was given. The remaining of the hamsters were painted three times per week for six weeks with 0.5% DMBA. Then, they were subdivided into: G.B 1: did not receive any treatment till 12th week. G.B 2, 3, 4: were painted by TQ, EGCG, and CUR 3 times/week for another 6 weeks respectively. In G.B1; 100% of hamsters revealed OSCC. In G.B2 (TQ); 16.6% hamsters showed superficial invasion, 33.3% revealed carcinoma in situ and 50% showed severe dysplasia. In G.B3 (EGCG), 66.6% of hamsters showed severe dysplasia and 33.3% exhibited moderate dysplasia. In G.B4 (CUR), 66.6% hamsters showed well-differentiated OSCC, and 33.3% revealed carcinoma in situ. Significant decrease of PCNA immunoreactivity in GA, GB3, and GB2 (8.9 ± 2.2, 16.1 ± 2.4, and 32.5 ± 1.3 respectively) in comparison with G.B1 (53.7 ± 1.4). While GB4, showed statistically significant decrease (40.7 ± 0.8) in comparison to G.B1. Significant increase of Caspase 3 expression in GB3, GB2, GB4, and GA (120.3 ± 2.1, 100 ± 3.1, 70.5 ± 0.9, and 59.9 ± 11.7 respectively) in comparison with G.B1. Topical EGCG had a superior therapeutic effect than TQ, and CUR against the progression of oral premalignant lesions.