Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional Ca²⁺/calmodulin-dependent kinase II (CaMKII) has emerged as a critical regulator of cardiac hypertrophy and failure, although the mechanisms remain unclear. Previous studies have established that the cytoskeletal protein β_IV-spectrin coordinates local CaMKII signaling. Here, we sought to determine the role of a spectrin-CaMKII complex in maladaptive remodeling in HF. Chronic pressure overload (6 weeks of transaortic constriction [TAC]) induced a decrease in cardiac function in WT mice but not in animals expressing truncated β_IV-spectrin lacking spectrin-CaMKII interaction (qv^3J mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in qv^3J TAC hearts. In vitro experiments demonstrated that β_IV-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific β_IV-spectrin–KO (β_IV-cKO) mice showed STAT3 dysregulation, fibrosis, and decreased cardiac function at baseline, similar to what was observed with TAC in WT mice. STAT3 inhibition restored normal cardiac structure and function in β_IV-cKO and WT TAC hearts. Our studies identify a spectrin-based complex essential for regulation of the cardiac response to chronic pressure overload. We anticipate that strategies targeting the new spectrin-based “statosome” will be effective at suppressing maladaptive remodeling in response to chronic stress.