The main challenge of cancer treatment is multidrug resistance during chemotherapy. Cancer cell can evade cell death during every round of orthodox chemotherapy drugs, consequently being resistant after several rounds of standard drug treatment. One of the regimens to address this multidrug resistance problem is by drug combination. However, synthetic drugs always have problems of strong side effects and toxicity. Natural compounds deriving from traditional Chinese medicine are known to have low toxicity and genuine promising effects in reversing multidrug resistance, either induced by orthodox chemotherapeutic or targeted therapy drugs. Numerous mechanisms including suppression of drug efflux, detoxifying systems, DNA repair systems, and anti-apoptosis pathways were responsible for such process. A range of natural compounds functioned on the suppression of apoptosis are widely reported, which include flavonoids, terpenoids, alkaloids, quinones, xanthones, saponins and polysaccharides. Here, this review summarized comprehensive data from in vitro and in vivo studies to elucidate the functional roles of natural compounds in reversing multidrug resistance during cancer therapy.