Natural products have shown significant potential in reversing cancer multidrug resistance (MDR). This review summarizes the mechanisms by which natural product-derived compounds combat MDR, focusing on flavonoids, alkaloids, terpenoids, polyphenols, and coumarins. MDR is a major challenge in cancer chemotherapy, as it leads to resistance against various anticancer drugs. Natural products can reverse MDR by modulating signaling pathways, altering drug targets, enhancing DNA damage repair, and affecting autophagy and the tumor microenvironment. Flavonoids, such as dihydromyricetin, apigenin, and wogonin, inhibit P-gp and other drug efflux pumps, increase drug uptake, and induce apoptosis in cancer cells. They also modulate signaling pathways like NF-κB and PI3K/AKT, which are involved in drug resistance. Alkaloids like lycorine, securinega alkaloids, and tetrandrine inhibit P-gp and other transporters, reduce drug resistance, and promote apoptosis in cancer cells. Polyphenols such as resveratrol, curcumin, and epigallocatechin-3-gallate (EGCG) inhibit P-gp, enhance drug uptake, and modulate signaling pathways like NF-κB and PI3K/AKT. They also induce DNA damage and apoptosis in cancer cells. Terpenoids and coumarins also play a role in reversing MDR. For example, β-elemene inhibits P-gp, reduces drug resistance, and induces apoptosis in cancer cells. Coumarins like PFC inhibit ABCG2/BCRP-mediated drug transport and reduce drug resistance in cancer cells. These natural products can overcome MDR by targeting multiple pathways, including drug efflux, DNA repair, and autophagy. Their ability to modulate these pathways makes them promising candidates for overcoming MDR in cancer therapy.Natural products have shown significant potential in reversing cancer multidrug resistance (MDR). This review summarizes the mechanisms by which natural product-derived compounds combat MDR, focusing on flavonoids, alkaloids, terpenoids, polyphenols, and coumarins. MDR is a major challenge in cancer chemotherapy, as it leads to resistance against various anticancer drugs. Natural products can reverse MDR by modulating signaling pathways, altering drug targets, enhancing DNA damage repair, and affecting autophagy and the tumor microenvironment. Flavonoids, such as dihydromyricetin, apigenin, and wogonin, inhibit P-gp and other drug efflux pumps, increase drug uptake, and induce apoptosis in cancer cells. They also modulate signaling pathways like NF-κB and PI3K/AKT, which are involved in drug resistance. Alkaloids like lycorine, securinega alkaloids, and tetrandrine inhibit P-gp and other transporters, reduce drug resistance, and promote apoptosis in cancer cells. Polyphenols such as resveratrol, curcumin, and epigallocatechin-3-gallate (EGCG) inhibit P-gp, enhance drug uptake, and modulate signaling pathways like NF-κB and PI3K/AKT. They also induce DNA damage and apoptosis in cancer cells. Terpenoids and coumarins also play a role in reversing MDR. For example, β-elemene inhibits P-gp, reduces drug resistance, and induces apoptosis in cancer cells. Coumarins like PFC inhibit ABCG2/BCRP-mediated drug transport and reduce drug resistance in cancer cells. These natural products can overcome MDR by targeting multiple pathways, including drug efflux, DNA repair, and autophagy. Their ability to modulate these pathways makes them promising candidates for overcoming MDR in cancer therapy.