BACKGROUND: A form of cancer that affects the rectum or colon (large intestine) is called colorectal cancer (CRC). The main risk factors for CRC include dietary, lifestyle, and environmental variables. Currently natural polyphenols have demonstrated impressive anticarcinogenic capabilities. OBJECTIVE: The main objective was to provide an updated, thorough assessment of the defensive mechanism of natural polyphenols for the global suppression of colorectal cancer. More precisely, this study aimed to analyze a set of chosen polyphenols with demonstrated safety, effectiveness, and biochemical defense mechanism on colon cancer models in order to facilitate future research. METHODS: This review was carried out with purposefully attentive and often updated scientific databases, including PubMed, Scopus, Science Direct, and Web of Science. After selecting approximately 178 potentially relevant papers based just on abstracts, 145 studies were meticulously reviewed and discussed. RESULTS: The outcomes disclosed that anti-CRC mechanisms of natural polyphenols involved the control of several molecular and signaling pathways. Natural polyphenols have also been shown to have the ability to limit the growth and genesis of tumors via altering the gut microbiota and cancer stem cells. However, the biochemical uses of many natural polyphenols have remained restricted because of their truncated water solubility and low bioavailability. In order to attain synergistic properties it is recommended to combine the use of different natural polyphenols because of their low bioavailability and volatility. However, the use of lipid-based nano- and micro-carriers also may be helpful to solve these problems with efficient distribution system to target sites. CONCLUSION: In conclusion, the use of polyphenols for CRC treatment appears promising. To ascertain their efficacy, more clinical research is anticipated.