Some adipokines, such as adiponectin (ADPN), other than being implicated in the central regulation of feeding behavior, may influence gastric motor responses, which are a source of peripheral signals that also influence food intake. The present study aims to elucidate the signaling pathways through which ADPN exerts its actions in the mouse gastric fundus. To this purpose, we used a multidisciplinary approach. The mechanical results showed that ADPN caused a decay of the strip basal tension, which was abolished by the nitric oxide (NO) synthesis inhibitor, L-N-nitro arginine (L-NNA). The electrophysiological experiments confirmed that all ADPN effects were abolished by L-NNA, except for the reduction of Ca current, which was instead prevented by the inhibitor of AMP-activated protein kinase (AMPK), dorsomorphin. The activation of the AMPK signaling by ADPN was confirmed by immunofluorescence analysis, which also revealed the ADPN R1 receptor (AdipoR1) expression in glial cells of the myenteric plexus. In conclusion, our results indicate that ADPN exerts an inhibitory action on the gastric smooth muscle by acting on AdipoR1 and involving the AMPK signaling pathway at the peripheral level. These findings provide novel bases for considering AMPK as a possible pharmacologic target for the potential treatment of obesity and eating disorders.