【Abstract】 Objective To explore the effect of SOX21 on gastric cancer (GC) and its possible mechanism. Methods A total of 44 cases of GC tissue and corresponding adjacent tissues were collected. Gastric cancer cell line AGS and human gastric mucosal epithelial cell line GES-1 were used as further research objects. Methylationspecific PCR was used to detect SOX21 methylation status. qRT-PCR, immunohistochemistry (IHC) and Western blot were used to detect the expression of SOX21 and Wnt/β-catenin pathway related gene. CCK8 kit and clone formation experiments were used to detect cell proliferation ability. The flow cytometry was used to detect cell apoptosis. Transwell was used to detect cell migration and invasion ability. Results Compared with the adjacent tissues, the methylation rate of SOX21 in GC tissue was significantly increased (P＜0.001), and the SOX21 IHC score, mRNA expression and protein expression were significantly reduced (P＜0.05). SOX21 was demethylated in GES-1 cells, but fully methylated in AGS. Compared with the GES-1 group, the SOX21 mRNA and protein expressions in the AGS group were significantly reduced (P＜0.05). Compared with the NC group, SOX21 mRNA expression, protein expression and apoptosis rate were significantly increased in SOX21 group (P＜0.05), cell viability, number of clone formation, number of migration and invasion cells were significantly reduced (P＜0.05), β -catenin, c-myc, cyclinD1 and MMP7 protein expression was significantly reduced (P＜0.05). Conclusion SOX21 is hypermethylated and its expression is reduced in gastric cancer tissues. Overexpression of SOX21 may inhibit the proliferation, migration and invasion of gastric cancer cells and promote cell apoptosis by inhibiting the Wnt/β-catenin pathway.