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Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. P‐glycoprotein (P‐gp) one of the ATP‐binding cassette (ABC) transporters plays an important role in MDR. In this study, we examined the sensitizing property of andrographolide (Andro) to reverse MDR in the drug‐resistant KBChR 8‐5 cells. Andro exhibited increased cytotoxicity in a concentration‐dependent manner in the P‐gp overexpressing KBChR 8‐5 cells. Furthermore, Andro showed synergistic interactions with PTX and DOX in this drug‐resistant cells. Andro co‐administration enhanced PTX‐ and DOX‐induced cytotoxicity and reduced cell proliferation in the MDR cancer cells. Moreover, reactive oxygen species (ROS) were elevated with a decrease in the mitochondrial membrane potential (MMP) during Andro and chemotherapeutic drugs combination treatment in the drug‐resistant cells. Furthermore, Andro and PTX‐induced cell cycle arrest was observed in the drug‐resistant cell. We also noticed that the expression of ABCB1 and AKT were downregulated during Andro (4 µM) treatment. Furthermore, Andro treatment enhanced the expression of caspase 3 and caspase 9 in the combinational groups that support the enhanced apoptotic cell death in drug‐resistant cancer cells. Therefore, the results reveal that Andro plays a role in the reversal of P‐gp‐mediated MDR in KBChR 8‐5 cells which might be due to regulating ABCB1/AKT signaling pathway. Significance statement: ATP‐binding cassette (ABC) transporters‐mediated multidrug resistance (MDR) is a major hindrance during cancer treatment. Efflux mechanism of P‐glycoprotein (P‐gp) decreases bioavailability and efficacy of chemotherapeutic drugs. Already known inhibitors of P‐gp exhibit higher toxicity to the untargeted cells. Phytochemicals have great potential to reverse the MDR mechanism in cancer cells with less toxicity. Andrographolide (Andro), a phytochemical of Andrographis paniculata, enhanced the efficacy of the chemotherapeutic drugs and reverses drug resistance in MDR cancer cells. Therefore, Andro can be considered as a potent candidate to overcome MDR after preclinical and clinical validations. [ABSTRACT FROM AUTHOR]