Chemotherapy resistance is still a serious problem in the treatment of most cancers. Many cellular and molecular mechanisms contribute to both inherent and acquired drug resistance. They include the use of unaffected growth-signaling pathways, changes in the tumor microenvironment, and the active transport of medicines out of the cell. The antioxidant capacity of polyphenols and their potential to inhibit the activation of procarcinogens, cancer cell proliferation, metastasis, and angiogenesis, as well as to promote the inhibition or downregulation of active drug efflux transporters, have been linked to a reduced risk of cancer in epidemiological studies. Polyphenols also have the ability to alter immunological responses and inflammatory cascades, as well as trigger apoptosis in cancer cells. The discovery of the relationship between abnormal growth signaling and metabolic dysfunction in cancer cells highlights the importance of further investigating the effects of dietary polyphenols, including their ability to boost the efficacy of chemotherapy and avoid multidrug resistance (MDR). Here, it is summarized what is known regarding the effectiveness of natural polyphenolic compounds in counteracting the resistance that might develop to cancer drugs as a result of a variety of different mechanisms.