Objectives: The current investigation was conducted to examine the anticancer effect of polyisoprenoids from Avicennia marina and Avicennia lanata leaves in WiDr cells. Selectivity index (SI), cell cycle inhibition, and apoptosis activity were evaluated. Materials and Methods: The anticancer activity of polyisoprenoids from A. marina and A. lanata leaves was determined by observing the activity of these compounds toward WiDr cells using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay. The SI was determined from the IC50 of the polyisoprenoid extract in normal cells (Vero) versus cancer cells (WiDr). Inhibited cell cycle and increased apoptosis were analyzed by flow cytometry. Results: Polyisoprenoid extract from A. marina and A. lanata leaves exhibited anticancer activity against WiDr cells with an IC50 of 154.987 μg/mL and 305.928 μg/mL, respectively. The polyisoprenoid extract from A. marina leaves had an SI value of 5.195 (>3) for categorization as exceptionally selective. Cell cycle analysis revealed that the inhibition occurred in the G0–G1 phase and apoptosis occurred in the early-apoptosis development. Conclusion: Polyisoprenoids from A. marina and A. lanata leaves can be used as anticancer agents against WiDr colon cancer cells. The mechanisms that underlie anticancer activity of the extract were due to by inhibiting of cell cycle and inducing of apoptosis.