Epithelial-to-mesenchymal transition (EMT) is considered to play an essential role in progression and metastasis. This study aims to investigate the expression and underlying molecular targets of high-mobility group AT-hook 2 (HMGA2) in the progression of colon cancer. The expression of HMGA2 is upregulated by both active extracellular signal-regulated kinase (ERK)1/2 and TGF-β signaling in colon cancer cells through a series of lentiviral infection and pharmacological assays. HMGA2 knockdown by specific shRNAs attenuates proliferation, motility and invasion of colon cancer cells in vitro and in vivo. Besides, exogenous HMGA2 expression caused EMT in colon cancer cells, which was confirmed by the downregulation of the epithelial markers and the upregulation of the mesenchymal markers. Moreover, HMGA2 positively regulates the Slug expression by directly binding to the regulatory region in Slug promoter. Importantly, the knockdown of Slug could reverse the HMGA2-induced EMT and decrease the migration and invasion ability of colon cancer cells. Taken together, our results reveal a critical role for HMGA2 in promoting EMT, migration, invasion, and proliferation of colon cancer cells, suggesting HMGA2 as a potential molecular target to prevent colon cancer progression.