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Simple Summary: Globally, colorectal cancer (CRC) is a leading cause of cancer deaths and chemotherapy, in combination with radiotherapy when appropriate, is used to treat the majority of CRC patients. However, the acquisition or development of drug resistance can decrease, or even abolish, the efficacy of chemotherapy. ATP-binding cassette (ABC) transporters, particularly, the ABCB1 and ABCG2 transporter, are mediators of multidrug resistance (MDR) in certain types of cancer cells. The aim of our in vitro study was to determine if poziotinib can overcome MDR to certain chemotherapeutic drugs in colon cancer cells. Our results indicated that in MDR CRC cell lines, poziotinib inhibits the transport function of the ABCB1 and ABCG2 transporters, increasing the intracellular accumulation of certain anticancer drugs, and thus, their efficacy. Furthermore, poziotinib decreased the expression of the ABCG2 protein. Therefore, if our results can be translated to humans, they suggest that using poziotinib in combination with certain anticancer drugs may be of therapeutic benefit in colorectal cancer patients. Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Currently, chemotherapy is a first-line treatment for CRC. However, one major drawback of chemotherapy is the emergence of multidrug resistance (MDR). It has been well-established that the overexpression of the ABCB1 and/or ABCG2 transporters can produce MDR in cancer cells. In this study, we report that in vitro, poziotinib can antagonize both ABCB1- and ABCG2-mediated MDR at 0.1–0.6 μM in the human colon cancer cell lines, SW620/Ad300 and S1-M1-80. Mechanistic studies indicated that poziotinib increases the intracellular accumulation of the ABCB1 transporter substrates, paclitaxel and doxorubicin, and the ABCG2 transporter substrates, mitoxantrone and SN-38, by inhibiting their substrate efflux function. Accumulation assay results suggested that poziotinib binds reversibly to the ABCG2 and ABCB1 transporter. Furthermore, western blot experiments indicated that poziotinib, at 0.6 μM, significantly downregulates the expression of the ABCG2 but not the ABCB1 transporter protein, suggesting that the ABCG2 reversal effect produced by poziotinib is due to transporter downregulation and inhibition of substrate efflux. Poziotinib concentration-dependently stimulated the ATPase activity of both ABCB1 and ABCG2, with EC50 values of 0.02 μM and 0.21 μM, respectively, suggesting that it interacts with the drug-substrate binding site. Molecular docking analysis indicated that poziotinib binds to the ABCB1 (−6.6 kcal/mol) and ABCG2 (−10.1 kcal/mol) drug-substrate binding site. In summary, our novel results show that poziotinib interacts with the ABCB1 and ABCG2 transporter, suggesting that poziotinib may increase the efficacy of certain chemotherapeutic drugs used in treating MDR CRC. [ABSTRACT FROM AUTHOR]