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Background: Plant derived compounds have provided proming leads in search for safer anticancer chemotherapies. Zanthoxylum zanthoxyloides is a common medicinal plant in Uganda whose bioactive composition has not been fully elucidated. The aim of this study was to evaluate the in vitro antiproliferative potential of compounds isolated from Zanthoxylum zanthoxyloides and their probable in silico anticancer mechanisms of action. Methods: Column chromatography was used to isolate compounds from MeOH:CH2Cl2 (1:1) extract of the stem bark extract of Zanthoxylum zanthoxyloides. The structures of the isolated compounds were elucidated by NMR and MS analyses. MTT assay was used to measure cell viability. Using in silico docking, the interaction of the compounds with key target proteins in the p53 pathway was determined. Results: From the root bark of this plant five compounds were isolated, namely; dihydrochelerythrine (1), skimmianine (2), tridecan-2-one (3), sesamin (4) and hesperidin (5). Dihydrochelerythrine (1) inhibited proliferation of liver cancer (HCC) cells (IC50 21.2), breast cancer (BT549) cells, (IC50 21.2 µM). Similarly, sesamin (4) exhibited moderate inhibitory activity against BT549 cancer cells (IC50 47.6 µM). Hesperidin (5) showed low inhibitory activity against A549 and HEp2 (Larynx) cells but was significantly toxic to normal liver and lung cells. In silico docking studies showed that all the compounds strongly bind to cyclin-dependent kinases (CDK2 and CDK6) and weakly bind to caspases 3 and 8 suggesting that they inhibit cancer cells by inducing cell cycle arrest and apoptosis. Conclusion: This study indicates that the compounds isolated from Z. zanthoxyloids hold promise as potential leads against cancer. Due to high toxicity of compound 5 against normal lung and liver cells, it deserves further toxicity investigations to access its safety before in vivo trials. [ABSTRACT FROM AUTHOR]