In the present study, we revealed that: (a) the expression of TRPV1 channel at the levels of mRNA and proteins was significantly decreased in human primary GC tissues; (b) the downregulation of TRPV1 expression was closely correlated with poor GC progression; (c) TRPV1 inhibited proliferation, migration and invasion of GC cells in vitro, and reduced gastric tumor size, number and peritoneal dissemination in vivo; and (d) mechanistically, TRPV1 suppresses GC progression through Ca2+/CaMKKβ/AMPK signaling pathway to reduce cyclin D1 and MMP2 expression. Here, MMP2 is linked to gastric neoplasm.