Identified over a dozen years ago in the brain and pancreatic islet, β_IV-spectrin is critical for the local organization of protein complexes throughout the nervous system. β_IV-Spectrin targets ion channels and adapter proteins to axon initial segments and nodes of Ranvier in neurons, and β_IV-spectrin dysfunction underlies ataxia and early death in mice. Despite advances in β_IV-spectrin research in the nervous system, its role in pancreatic islet biology is unknown. Here, we report that β_IV-spectrin serves as a multifunctional structural and signaling platform in the pancreatic islet. We report that β_IV-spectrin directly associates with and targets the calcium/calmodulin-dependent protein kinase II (CaMKII) in pancreatic islets. In parallel, β_IV-spectrin targets ankyrin-B and the ATP-sensitive potassium channel. Consistent with these findings, β_IV-spectrin mutant mice lacking CaMKII- or ankyrin-binding motifs display selective loss of expression and targeting of key protein components, including CaMKIIδ. β_IV-Spectrin–targeted CaMKII directly phosphorylates the inwardly-rectifying potassium channel, Kir6.2 (alpha subunit of K_ATP channel complex), and we identify the specific residue, Kir6.2 T224, responsible for CaMKII-dependent regulation of K_ATP channel function. CaMKII-dependent phosphorylation alters channel regulation resulting in K_ATP channel inhibition, a cellular phenotype consistent with aberrant insulin regulation. Finally, we demonstrate aberrant K_ATP channel phosphorylation in β_IV-spectrin mutant mice. In summary, our findings establish a broader role for β_IV-spectrin in regulation of cell membrane excitability in the pancreatic islet, define the pathway for CaMKII local control in pancreatic beta cells, and identify the mechanism for CaMKII-dependent regulation of K_ATP channels.