Colorectal cancer is among the most common and deadliest types of cancers affecting humans and animals. Currently, chemotherapeutic and radiotherapeutic measures are being practiced in treating it but they have devastating side effects including cardiopathologies and nephropathologies.  Moreover, they are unreliable and can not provide complete treatment in advanced cases. These scenarios necessitate therapeutic substances for the prevention and treatment of colorectal cancer. Plant-based compounds, especially various types of phenolics are among the most considered substances as alternatives to prevent and treat colorectal cancer. Among all the phenolics, multiple compounds belonging to flavonoids, flavone, flavonol, and stilbenes have been found effective in treating and preventing colorectal cancer. Predisposing factors that lead to the development of colorectal cancer depend upon living type, feeding type, genotype, age, gender, and exposure to carcinogens. All the polyphenolics prevent colorectal cancer by detoxifying carcinogens, oxidative stress management, reduction in preneoplastic lesions. Specifically, quercetin can arrest S, G1/S, and other stages of cancerous cells, resveratrol controls cancerous cell proliferation and detoxifies the pathological effects of anticancer therapeutic agents by regulating several enzyme systems, and kaempferols control aging process, and uncontrolled metastasis by regulating relevant enzyme systems. All these polyphenolics arrest cancer metastasis by limiting abnormal cell division, preventing extracellular skeletal system damage, and several other pathways. Additionally, they have been found safe for all the systems of the body which is their advantage over current cancer therapies.  All of these have passed in vitro trials and proven effective. Currently, xenograft rodent models are being used and these in vivo models also approve their therapeutic use of some polyphenolics i.e., resveratrol and kaempferol are being clinically used as synergists to chemotherapeutic substances. This review highlights the potential of selected polyphenolics as preventive and cancer-treating substances in the light of in vivo studies in rodent models.