The article reviews the role of natural products in reversing cancer multidrug resistance (MDR). MDR is a significant challenge in cancer treatment, as it reduces the effectiveness of chemotherapy. The review highlights the mechanisms by which natural products, including flavonoids, alkaloids, terpenoids, polyphenols, and coumarins, can overcome MDR. These compounds regulate signaling pathways, target specific proteins or genes, and enhance cellular uptake of anticancer drugs. Key mechanisms include inhibiting drug efflux pumps, altering drug targets, increasing DNA damage repair, and modulating non-coding RNA activity. The review also discusses the impact of autophagy and the tumor microenvironment on MDR and how natural products can address these issues. Specific examples of natural products and their mechanisms of action are provided, emphasizing their potential as multifunctional agents in cancer therapy. The conclusion underscores the importance of natural products in overcoming MDR and improving chemotherapy outcomes.The article reviews the role of natural products in reversing cancer multidrug resistance (MDR). MDR is a significant challenge in cancer treatment, as it reduces the effectiveness of chemotherapy. The review highlights the mechanisms by which natural products, including flavonoids, alkaloids, terpenoids, polyphenols, and coumarins, can overcome MDR. These compounds regulate signaling pathways, target specific proteins or genes, and enhance cellular uptake of anticancer drugs. Key mechanisms include inhibiting drug efflux pumps, altering drug targets, increasing DNA damage repair, and modulating non-coding RNA activity. The review also discusses the impact of autophagy and the tumor microenvironment on MDR and how natural products can address these issues. Specific examples of natural products and their mechanisms of action are provided, emphasizing their potential as multifunctional agents in cancer therapy. The conclusion underscores the importance of natural products in overcoming MDR and improving chemotherapy outcomes.