Zanthoxylum simulans Hance. is known in folklore as a spicy herb, commonly used to treat cold-induced diseases in the body. In this study, we evaluated the cytotoxic effects of Zanthoxylum simulans fruit bark extract. Samples of Zanthoxylum simulans were extracted with 70% ethanol and subsequently fractionated with n-Hexane, ethyl acetate (EtOAc), and n-butanol (n-BuOH) solvents. To evaluate the in vitro cytotoxic effect, we performed SRB (Sulforhodamine B) assay on the cell lines of human gastric MKN-7. In this study, we also used molecular docking method to evaluate the inhibition abilities of MAPK1 and AKT1 receptors of 120 compounds in Zanthoxylum simulans Hance. The in vitro cytotoxic results showed that the n-Hexane total extract had the strongest cytotoxicity effects on gastric cancer cells with an IC50 of 23.65±1.75 mg/ml. The results cytotoxic effects on MNK-7 gastric cancer cells of these fractions showed that the EtOAc and EtOH fractions exhibited activity with IC50 values of 35.61±2.90 and 50.67±3.82 µg/mL, respectively; while the BuOH and H2O fractions showed no activity. The molecular docking results showed five compounds that inhibit both MAPK1 and AKT1 targets including Simulanoquinoline, N-acetylanonaine, N-acetyldehydroanonaine, Oxyavicine, and Benzosimuline. Therefore, our results showed that Zanthoxylum simulans fruit bark extract has a strong cytotoxicity effect on gastric cancer cells. In vivo studies of these potential compounds should be carried out to become anti-cancer drugs in the future.