The worldwide incidence and mortality of gastric cancer remain high, and thus, new treatment concepts are needed. Quercetin, a bioflavonoid, has been proposed to have anti-cancer properties. The aim of this study was to determine the nature of the apoptotic mechanism responsible for the action of quercetin in AGS cells (a commonly used human gastric adenocarcinoma cell line). AGS cell viabilities were assessed using a MTT assay and flow cytometric analysis, mitochondrial membrane depolarization, and caspase-3 were used to check the involvement of apoptosis. Whole-cell configuration patch-clamp experiments were used to regulate the transient receptor potential melastatin (TRPM) 7 channels. To investigate the signaling pathway of quercetin-induced apoptosis in AGS cells, western blotting and MTT assays were used. Quercetin was found to induce the apoptosis of these cells, and this apoptosis was inhibited by SB203580 (p38 kinase inhibitor), SP600125 (JNK inhibitor) and PD98059 (ERK inhibitor). In addition, quercetin inhibited TRPM7 currents in AGS cells and in human embryo kidney (HEK) 293 cells overexpressed TRPM7 channels. Furthermore, quercetin treatment increased TRPM7 overexpressing HEK293 cell death, indicating that TRPM7 channel upregulation underlies quercetin-induced cell death. These results suggest that quercetin plays an important pathophysiologic role in AGS cells via mitogen activated protein kinase (MAPK) signaling and TRPM7 channels, and that quercetin has potential as a pharmacological treatment for gastric cancer.