Polyphenols (PPs) are secondary metabolites that are present in more than 80% of plants. They possess a plethora of medicinal properties by modulating key pathological pathways, including epigenetics and those involved in oncogenesis or tumorigenesis. PPs have been shown to inhibit tumor cell proliferation, metastasis, and cancer cell resistance to chemotherapeutic medications. Their coadministration, either as plant-rich extracts or in advanced pharmaceutical formulations like nano-formulations, significantly impacts the tolerability, efficiency, and cytotoxicity of traditional chemotherapeutic drugs. Both clinical and preclinical studies, including in vitro and in vivo models, demonstrated the potent anticancer activity of PPs. Combining PPs with conventional chemotherapeutic agents has led to a significant improvement in the efficiency and safety index of these agents. Advances in PP nano-formulations have enhanced their bioavailability and therapeutic efficacy. The current chapter highlights the potential of PPs and recent advances in their formulation for targeting cancer.