With increasing use of natural plant-derived components, exploring the anti-proliferative effects of phytochemicals is increasingly gaining importance in designing anticancer drugs. Quercetin, a natural constituent abundantly present in food products, is capable of inducing apoptosis in tumor cells. However, little is known about its biological effect on colon cancer cells and molecular mechanism leading to this event. The aim of this study was to investigate the effect of quercetin on the apoptotic pathway in human colon carcinoma cells (HT-29 cells). The results indicated that quercetin induced suppression of cell viability and apoptosis in HT-29 cells in a dose-dependent manner. This involved characteristic changes in nuclear morphology, activation of caspases-3 and caspases-9, collapse of Mitochondrial membrane potential (DCm), upregulation of pro-apoptotic Bax, and downregulation of antiapoptotic Bcl-2 and Bcl-XL. Quercetin, which exerts anti-proliferative effect though different signaling pathways, is a classic candidate for anti-colon cancer drug design.