Epigenetic changes play significant roles in cancer development. UHRF1, an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene (TSG) silencing in several cancers. In a previous study, we found that UHRF1 promoted gastric cancer (GC) invasion and metastasis. However, the role and underlying mechanism of UHRF1 in GC carcinogenesis remain largely unknown. In the present study, we investigated UHRF1 expression and function in GC proliferation and explored its downstream regulatory mechanism. The results demonstrated that UHRF1 overexpression was an independent and significant predictor of GC prognosis. Downregulation of UHRF1 suppressed GC proliferation and growth in vitro and in vivo, and UHRF1 upregulation showed opposite effects. Furthermore, downregulation of UHRF1 reactivated 7 TSGs, including CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML, via promoter demethylation. These results provide insight into the GC proliferation process, and suggest that targeting UHRF1 represents a new therapeutic approach to block GC development.