The study highlights for the first time the potential role of Caryota mitis and Caryota urens (family Arecaceae) in cancer chemoprevention as NQO1 enzyme inducers. Among the tested leaf extracts of different solvent polarities, C. urens petroleum ether leaf extract showed the most potent induction of NQO1 enzyme activity (4.79 times to vehicle control) via DCPIP assay and a significant difference was observed at concentration 25 μg/mL via NQO1 western blot analysis. First comparative GC/MS analysis of both species' petroleum ether leaf extracts was conducted to reveal for 35 vs 34 compounds in C. mitis and C. urens unsaponifiable matter, respectively, and 29 vs 15 fatty acids as methyl esters, respectively. Isolation attempts from the active C. urens extract resulted in the identification of five compounds i.e. oleanolic acid (T1), ursolic acid (T2), α-tocopherol (T3), palmitic and stearic acids (T4 & T5) using different spectroscopic techniques; where T1 and T3 are first time to be identified in C. urens. Assessment of the isolated compounds' chemopreventive activity was conducted via in silico molecular modeling against KEAP-1 –Nrf2 complex involved in of NQO1 where T1, T2 and T3 showed promising docking score of -7.7, -7.9 and -7.05 kcal/mol, respectively, compared to -8.2 kcal/mol for 4'-bromoflavone as a positive control.