BACKGROUND: Gastric cancer (GC) is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. MAM Domain Containing 2 (MAMDC2) has been involved in many cancers. However, the impact of MAMDC2 on gastric cancer was unclear. This study aimed to investigate the role and mechanism of MAMDC2 in gastric cancer. METHODS: Differential genes in gastric cancer are analyzed by GEO, TCGA, MSigDB database, R-packet limma, and Wilcoxon test. Survival analysis is performed through the R package survival. Construct a PPI network through the STRING database. Enrichment analysis is performed by Metascape. The infiltration level of gastric cancer immune cells is calculated by CIBERSORT. In addition, the expression of MAMDC2 was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction (RT-qPCR). siMAMDC2 was used to knock down the specific gene. Cell counting kit-8 (CCK-8) assay, colony formation assay, and cell migration were applied to evaluate the function of MAMDC2 in gastric cancer cells. RESULTS: In the present study, we revealed a significant upregulation of MAMDC2 in gastric cancer tissues and cells. Knocking down MAMDC2 inhibited the proliferation and migration of gastric cancer cells, while overexpression of MAMDC2 produced the opposite results. Furthermore, MAMDC2 may be an independent factor in poor prognosis in gastric cancer patients. CONCLUSION: These results illustrated that MAMDC2 promoted the proliferation and migration of gastric cancer cells. The newly identified MAMDC2 provides novel insight into the pathogenesis of gastric cancer.