<p>Colorectal cancer continues to be a major contributor to global cancer-related mortality, highlighted the vital need for more effective and safer therapeutic approaches. This study examines the plant of <i>Polygonum minus</i> (<i>P. minus</i>) extracts and their cytotoxic effect on normal cell and colon cancer cell lines, focusing on the selectivity index and potential therapeutic viability of these extracts. Sequential extraction was performed using several solvents such as hexane, dichloromethane (DCM), methanol, and water, resulted in varying extraction yields; methanol (18.5%) and water (17.3%) provided the highest yields. For colon cancer SW480 cell line, both hexane and water extracts demonstrated the highest cytotoxicity with a significant reduction in cell viability from (26–16) % within (24–72) hour, which led to an outperformance for the DCM extracts. The methanol extract exhibited cytotoxicity comparable to that of the hexane and water extracts only at 72&#xa0;h. In contrast, in the SW620 cell line, the DCM extract demonstrated the greatest cytotoxic effect, reducing cell viability to 26.44% at 72&#xa0;h and markedly surpassing the activity of the hexane extract. The methanol and water extracts showed cytotoxicity levels similar to the DCM extract at this time point, whereas the hexane extract produced the weakest response. Notably, the water extract showed a high selectivity index, indicating its preferential cytotoxicity towards cancer cells compared with normal HS-27 cells and highlighted its potential as a safer therapeutic option. This selective cytotoxicity, particularly evident in these extracts, particularly the water extract, is likely attributed to its enriched phenolic compounds, including quercetin, rutin, gallic acid, and kaempferol derivatives. These findings highlight the importance of natural plant (<i>P. minus</i>) as anticancer agents by providing safer, and more effective treatments for colorectal cancer.</p>