Tumor metastases are the ultimate target in cancer therapy. In epithelial malignancies, the expression of high-mobility-group A2 (HMGA2) is associated with disease progression and the epithelial-mesenchymal transition (EMT), which is involved in the metastatic process. The present study assessed the clinical and molecular effects of HMGA2 with the malignant tissues of 170 patients with gastric cancer and gastric cancer cells expressing HMGA2. HMGA2 expression was determined using immunohistochemistry and analyzed with respect to the clinicopathological data of patients with this tumor. In the gastric cancer cell line MKN28, in which HMGA2 was knocked down by two different short-hairpin RNAs, Transwell migration and invasion assays were conducted and western blotting was used to detect the altered expression of EMT markers. In patients with gastric cancer, HMGA2 overexpression correlated with tumor progression and was indicative of a significantly worse overall survival. Migration and invasion assays using HMGA2-knocked down MKN28 cells showed a reduction in cell migration and invasion. The upregulation of E-cadherin, an epithelial marker, and the downregulation of N-cadherin, a mesenchymal marker were observed in HMGA2-knocked down cells. In addition, expression of the transcriptional factors Snail and Zeb1 and of the EMT-pathway molecule β-catenin were decreased. HMGA2 overexpression, through its relationship to EMT, thus seems to aggravate invasion and metastasis in gastric cancer. It may therefore serve as a predictive marker in determining the clinical outcome of patients with gastric cancer and offer a promising therapeutic target.