The transcription factor twist family bHLH transcription factor 1 (TWIST), which is a member of the basic helix-loop-helix class of proteins, is known to induce epithelial-mesenchymal transition (EMT) and promote cancer metastasis. TWIST has previously been reported to be associated with multidrug resistance (MDR), since its depletion increases drug sensitivity. Although these previous studies have established a strong association between EMT and MDR, the molecular mechanism remains obscure. The present study demonstrated that TWIST protein expression was elevated in liver cancer, and was positively correlated with multidrug resistance protein 1 (MDR1) expression. Conversely, MDR1 was negatively correlated with E‑cadherin expression in liver cancer samples. In addition, the present study indicated that doxorubicin-resistant HepG2 (R‑HepG2) cells acquired an EMT phenotype. TWIST was also more highly expressed in R‑HepG2 cells compared with in parental HepG2 cells. Knockdown of TWIST increased the sensitivity of R‑HepG2 cells to 5-fluroracil, cisplatin and doxorubicin through a reduction in MDR1 expression and drug efflux ability. Furthermore, knockdown of TWIST in R‑HepG2 cells inhibited the migratory ability of cells and suppressed the EMT phenotype. These findings demonstrated that targeting TWIST may be considered a novel strategy to overcome drug resistance in liver cancer.