Inhibition of tumor metastasis is one of the most important purposes in colorectal cancer (CRC) treatment. This study aimed to explore the effects of liquiritigenin, a flavonoid extracted from the roots of Glycyrrhiza uralensis Fisch, on HCT116 cell proliferation, invasion, and epithelial-to-mesenchymal transition (EMT). We found that liquiritigenin significantly inhibited HCT116 cell proliferation, invasion, and the EMT process, but had no influence on cell apoptosis. Moreover, liquiritigenin remarkably reduced the expression of runt-related transcription factor 2 (Runx2) in HCT116 cells. Overexpression of Runx2 obviously reversed the liquiritigenin-induced invasion and EMT inhibition. Furthermore, liquiritigenin inactivated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway in HCT116 cells. Upregulation of Runx2 reversed the liquiritigenin-induced PI3K/AKT pathway inactivation. In conclusion, our research verified that liquiritigenin exerted significant inhibitory effects on CRC invasion and EMT process by downregulating the expression of Runx2 and inactivating the PI3K/AKT signaling pathway. Liquiritigenin could be an effective therapeutic and preventative medicine for CRC treatment.