Cancer is one of the most serious diseases endangering human health. In view of the side effects caused by chemotherapy and radiotherapy, it is necessary to develop low-toxic anti-cancer compounds. Polyphenols are natural compounds with anti-cancer properties and their application is a considerable choice. Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. It is of great significance to clarify the mechanisms of polyphenols on tumor suppression by inducing senescence. In this review, we delineated the characteristics of senescent cells, and summarized the mechanisms of polyphenols targeting tumor microenvironment and inducing cancer cell senescence for cancer prevention and therapy. Although many studies have shown that polyphenols effectively inhibit cancer by targeting senescence, it warrants further investigation in preclinical and clinical studies.