Patients with colorectal cancer (CRC) often develop distant metastases, which significantly reduces the 5-year survival rate. Epithelial-mesenchymal transition (EMT) is a crucial process for the invasion and metastasis of cancer cells. Tetrandrine has been reported to inhibit the viability and EMT of CRC cells; however, to the best of our knowledge, the molecular mechanism remains undetermined.The MTT assay was used to determine HCT116 cell viability. Wound healing and Transwell assays were used to determine that cell migration and invasion, respectively. Western blotting analysis was performed to detect the expression of migration-related genes. Four different lengths of the E-cadherin gene promoter were constructed and cloned into pGL3 reporter plasmids to evaluate E-cadherin gene promoter activity.The results of the MTT assay revealed that tetrandrine inhibited HCT116 cell viability, with an IC50 value of 7.2 μM following 24 h of treatment. Tetrandrine inhibited IL-6-induced cell migration and invasion, respectively. Tetrandrine regulates the expression of migration-related genes in IL-6-stimulated HCT116 cells. Tetrandrine significantly downregulated the expression and enzyme activity of MMP-2 in IL-6-stimulated HCT116 cells. In addition, tetrandrine restored E-cadherin gene promoter activity.The findings of the present study suggested that tetrandrine may inhibit EMT in IL-6-stimulated HCT116 cells; therefore, it may represent a potential drug for CRC.