Pancreatic β-cell death and dysfunction contributes to the pathogenesis of both type 1 and type 2 diabetes. We aimed to examine whether the regulator of G protein signaling protein 2 (RGS2), a multifunctional inhibitor of G protein-coupled receptor (GPCR) signaling, impacts β-cell death and function. Metabolic phenotypes, β-cell secretory function, and glucose and insulin tolerance were measured in RGS2 knockout (RGS2-/-) mice and their wild-type (RGS2+/+) littermate controls. β-Cell death was evaluated in RGS2-knockdown and -overexpressing β cells and RGS2-/- islets by flow cytometry, western blot, ELISA, TUNEL staining, and apoptosis RT2 profiler PCR array analysis. β-Cell mass was evaluated in pancreases from RGS2-/- and RGS2+/+ mice at 1 day, 4 weeks, and 25 weeks of age. Our data show that RGS2-/- islets secreted more insulin than RGS2+/+ islets when challenged with glucose or exendin-4. RGS2-knockdown cells are susceptible to hypoxia induced cell death while RGS2-overexpressing cells are protected from cell death. Depletion of RGS2 in islets alters expression of apoptosis-related genes and RGS2-/- islets are prone to apoptosis compared with RGS2+/+ islets. Ultimately, excessive insulin secretion and increased β-cell apoptosis contributed to a 70% reduction in pancreatic β-cell mass in RGS2-/- mice compared with RGS2+/+ mice at 25 weeks of age. RGS2 has critical roles in maintaining pancreatic β-cell mass via modulating β-cell function and apoptosis. It may serve as a druggable target to help prevent pancreatic β-cell loss in the treatment of diabetes.