The use of naturally derived drugs in anti-cancer therapies has grown exponentially in recent years. Among natural compounds, polyphenols have shown potential therapeutic applications in treatment due to their protective functions in plants, their use as food additives, and their excellent antioxidant properties, resulting in beneficial effects on human health. Building more efficient cancer therapies with fewer side effects on human health can be achieved by combining natural compounds with conventional drugs, which are typically more aggressive than natural chemicals with polyphenols. This article reviews a wide variety of studies where polyphenolic compounds can play a key role as anticancer drugs, alone or in combination with other drugs. Moreover, the future directions of applications of various polyphenols in cancer therapy are shown.