ATP-regulated potassium (K_ATP) channel complexes of inward rectifier potassium channel (K_ir) 6.2 and sulfonylurea receptor (SUR) 1 critically regulate pancreatic islet β-cell membrane potential, calcium influx, and insulin secretion, and consequently, represent important drug targets for metabolic disorders of glucose homeostasis. The K_ATP channel opener diazoxide is used clinically to treat intractable hypoglycemia caused by excessive insulin secretion, but its use is limited by off-target effects due to lack of potency and selectivity. Some progress has been made in developing improved K_ir6.2/SUR1 agonists from existing chemical scaffolds and compound screening, but there are surprisingly few distinct chemotypes that are specific for SUR1-containing K_ATP channels. Here we report the serendipitous discovery in a high-throughput screen of a novel activator of K_ir6.2/SUR1: VU0071063 [7-(4-(tert-butyl)benzyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione]. The xanthine derivative rapidly and dose-dependently activates K_ir6.2/SUR1 with a half-effective concentration (EC₅₀) of approximately 7 μM, is more efficacious than diazoxide at low micromolar concentrations, directly activates the channel in excised membrane patches, and is selective for SUR1- over SUR2A-containing K_ir6.1 or K_ir6.2 channels, as well as K_ir2.1, K_ir2.2, K_ir2.3, K_ir3.1/3.2, and voltage-gated potassium channel 2.1. Finally, we show that VU0071063 activates native K_ir6.2/SUR1 channels, thereby inhibiting glucose-stimulated calcium entry in isolated mouse pancreatic β cells. VU0071063 represents a novel tool/compound for investigating β-cell physiology, K_ATP channel gating, and a new chemical scaffold for developing improved activators with medicinal chemistry.