Zn2+ is a divalent cation that is essential for many biological activities, as it influences many ion channels and enzymatic activities. Zn2+ can evoke G-protein-coupled receptor signaling via activation of the metabotropic zinc receptor ZnR/GPR39. In spite of evidence suggesting the presence of ZnR/GPR39 in salivary gland cells, there has been no evidence of ZnR/GPR39-mediated modulation of salivary gland function. Here we characterized the role of ZnR/GPR39 in human submandibular gland cells. A 0.25% ZnCl2 solution evoked secretion of unstimulated and stimulated whole saliva in humans. We found that ZnR/GPR39 is expressed in human submandibular glands and HSG cells. Zn2+ increased cytosolic Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner. Muscarinic antagonist had no effect on Zn2+-induced [Ca2+]i increase, which was completely blocked by the phospholipase C-β inhibitor. As with muscarinic agonist, Zn2+ also induced the translocation of aquaporin-5 (AQP-5) to the plasma membrane, which was drastically decreased in ZnR/GPR39-knockdown cells. These data suggest that the metabotropic Zn2+ receptor ZnR/GPR39 can modulate salivary secretion in human submandibular gland cells independent of muscarinic or histamine receptor signaling.