Background: Mangrove plants produce a polyisoprenoid compound. Polyisoprenoids have been proven to have anticancer properties. This study investigated the inhibitory activity of polyisoprenoids derived from the leaves of mangrove plants Avicennia alba and Avicennia lanata regarding the expression of PI3K, Akt1, mTOR, P53, and EGFR genes against human colorectal adenocarcinoma WiDr cells. Methods: Anticancer activity was tested through the MTT assay method performed on WiDr cells. The inhibited cell cycle and apoptosis were analysed by flow cytometry and double staining. Gene expression of PI3K, Akt1, mTOR, P53, and EGFR was observed using the RT-PCR method. Results: Cytotoxic activity against WiDr cells showed that the IC50 for A. alba and A. lanata was 258.14 ug/mL and 243.32 ug/mL, respectively. This indicated that their classification as anticancer agents was moderate. The cell cycle showed that inhibition of A. alba and A. lanata occurred in the late phase of apoptosis S (10.60 and 10.51%) and G2-M1 (22.05 and 23.84%), which was higher than negative and positive control cells. Furthermore, the polyisoprenoids derived from A. alba and A. lanata leaves exhibited anticancer activity in WiDr cells through the downregulated gene expression of PI3K, Akt1, mTOR, and EGFR as well as the upregulated gene expression of P53. Conclusion: This study demonstrated that polyisoprenoids obtained from A. alba and A. lanata leaves are promising chemopreventive agents for colon cancer.