Gastrointestinal hormones which are secreted by enteroendocrine cells play important role in the regulation of pancreatic β cell survival and insulin secretion. Here we demonstrated that cholecystokinin CCK-8s activates a G-protein-coupled receptor, CCKAR, and elevates both IP3 and cAMP levels. Under low-glucose condition, Gq-IP3 signaling contributes to the CCK-8s-induced insulin secretion, while Gs-cAMP signaling increases the CCK-8s-mediated insulin secretion greatly in high glucose conditions. CCK-8s also promotes the CCKAR/β-arrestin-1 formation in pancreatic β cells, and further activates ERK signaling. Using β-arrestin-1 siRNA-mediated knockdown cells and β-arrestin-1 knockout mice, we demonstrated that β-arrestin-1 mediates both CCK-8s-induced insulin secretion and the protective function in pancreatic β cells. The association of β-arrestin-1 and CCKAR mediates cytoplasmic late-phase ERK phosphorylation, then activates the p90RSK-phospho-Bad pathway, which contributes to the anti-apoptotic effect of CCK-8s. Further studies on biased signaling of CCKAR in pancreatic β cells will help developing biased CCKAR ligands.