The underlying molecular pathogenesis in gastric cancer remains poorly unknown. The transcription factor myocyte enhancer factor 2D (MEF2D) participates in the initiation and development of many human cancers. However, its potential roles in gastric cancer have surprisingly not been studied. In present study, we first explored MEF2's expression in gastric cancer, finding that only MEF2D rather than MEF2A, 2B, or 2C was elevated in gastric cancer clinical specimens. Furthermore, immunohistochemical analysis on the tissue samples obtained from 260 patients with gastric cancer revealed that MEF2D expression was significantly associated with the clinical stage, vascular invasion, metastasis, and tumor size. Gastric cancer patients with MEF2D expression showed a significantly shorter overall survival time compared with that of patients lacking of MEF2D. Multivariate analysis revealed that MEF2D expression was an independent prognostic factor for overall survival. These results indicated that MEF2D was a prognostic marker for gastric cancer. Notably, MEF2D silencing was able to reduce the proliferation and survival of gastric cancer cells. Further study revealed that MEF2D suppression significantly inactivated the oncogenic Wnt/beta-catenin pathway. Downregulation of MEF2D inhibited the tumorigenesis of gastric cancer cells in nude mice. Finally, MEF2D is a direct target of miR-19, which was found to be decreased in gastric cancer clinical specimens. Collectively, we found that miR-19/MEF2D/Wnt/beta-catenin regulatory network contributes to the growth of gastric cancer, hinting a new promising target for gastric cancer treatment.