Interferon regulatory factor 2 (IRF-2) plays the roles of an anti-oncogene in gastric cancer (GC). However, the mechanism remains unknow. The expression of IRF-2 in GC tissues and adjacent non-tumor tissues was found by immunohistochemistry (IHC) and the predictive values of IRF-2 for the prognosis of GC patients were explored. Cell function experiments and xenograft tumor growth in nude mice were performed to test the proliferation ability of the tumor in vitro and in vivo. Chromatin Immunoprecipitation assay (ChIP-Seq) was used to verify the direct target of IRF-2. We found that the IRF-2 expression was down regulated in GC tissues and was negatively correlated with prognosis of GC patients. IRF-2 could negatively affect GC cells proliferation in vitro and in vivo. ChIP-Seq assay showed IRF-2 could directly activate AMER1 transcription and regulate Wnt/β-catenin signaling pathway, which was validated by IHC both in tissue microarray and xenografted tumor tissues, western blot analysis, and cell function experiment. In conclusion, high expression of IRF-2 can inhibit tumor growth and affect the prognosis of patients through inhibiting Wnt/β-catenin signaling pathway by directly regulating AMER1 transcription in GC.