--- - |2 Abstract The Kv2.1 channel plays an important role in the regulation against pancreatic β‐cell dysfunctions. Therefore, it is regarded as a promising target for drug discovery against type 2 diabetes. In the present study, we found that the small molecule 4‐ethoxy‐N‐{[6‐(2‐thienyl)‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazin‐3‐yl]methyl}aniline (ETA), a novel Kv2.1 inhibitor, may be capable of promoting glucose‐stimulated insulin secretion and protecting from apoptosis in pancreatic INS‐832/13 cells. The assay of ETA on type 2 diabetic mice induced by high‐fat diet (HFD)/streptozocin (STZ) confirmed its potency in ameliorating glucose homeostasis. ETA administration reduced fasting blood glucose and glycated haemoglobin levels, improved oral glucose tolerance, and increased serum insulin levels in HFD/STZ mice. Mechanism study demonstrated that ETA protected INS‐832/13 cells involving the regulation against protein kinase B and extracellular‐regulated protein kinase 1/2 signalling pathways. Our study has confirmed the underlying regulation of Kv2.1 against β‐cell function and also addressed the potential of ETA as a lead compound in the treatment of type 2 diabetes mellitus. - 'Clinical and Experimental Pharmacology and Physiology, Volume 45, Issue 12, Page 1257-1264, December 2018. '