Chemotherapy is one of the main methods for cancer treatment. However, despite many advances in the design of anticancer drugs, their efficiency is limited due to their high toxicity and resistance of cells to chemotherapeutic drugs. In order to improve the cancer therapy, it is essential to use the compounds that can overcome drug resistance and increase treatment efficiency. Researchers have studied the effects of natural compounds for the controlling various drug resistance mechanisms. Curcumin is a natural phenolic compound which shows potent anticancer activities in different tumors, alone or as an adjuvant with other antitumor drugs to prevent or inhibit the survival and cancer progression by various mechanisms. The role of curcumin in overcoming drug resistance was followed by reviewing different applications of curcumin in cancer therapy. Afterward, the clinical impacts of curcumin, role of curcumin in decreasing drug resistance in different cancer cells and its mechanisms were discussed. It has been demonstrated that curcumin regulates signaling pathways in cancer cells, reduces the expression of proteins related to drug resistance, and increases the performance of antitumor drugs at various levels. Curcumin reverses multidrug resistance mechanisms and increases sensitivity of resistance cells to chemotherapy. This review mainly focuses on different mechanisms of drug resistance and curcumin as a nontoxic natural substance to eliminate the effects of drug resistance through modulation and controlling cell resistance pathways and eventually suggests curcumin as a potent chemosensitizer in cancers.