In response to cardiac injury or increased workload, the mammalian heart undergoes ventricular remodeling to maintain cardiac function. Initally, these changes are compensatory, although ultimately, they can lead to death of cardiomyocytes, ventricular dilation, and progression to heart failure. It is critical to understand the underlying mechanisms that regulate this transition, since it could identify new therapeutic targets. The role of the small GTPase Septin4 in the heart, and in regulating cardiac stress response is unknown. Previous research has implicated Septin 4 in regulation of Store Operated Calcium entry, as well as cell death regulation through a splice isoform (ARTS). We performed cardiac pressure overload in wild type controls and Septin 4 knockout (-/-) mice. Importantly, we did not detect differences in cardiac hypertrophy or function at baseline (57% ejection fraction in both groups). Four weeks following transverse aortic constriction (TAC), Septin4-/- mice showed improved cardiac function with higher ejection fraction (51%) compared to controls (40%), while the level of hypertrophy was similar. Furthermore, we detected reduced cleaved caspase-3 staining after TAC in Septin4-/- mice, due to inhibition of cardiomyocyte apoptosis in Septin4 -/- mice. Mechanistically, we detected increases in protein expression of both total and phosphorylated phospholamban and CaMKII in Septin4-/- mice, suggesting alterations in Calcium handling, and indicating compensatory signaling pathways were still active in Septin4-/- mice, while control mice were transitioning to heart failure. In conclusion, genetic deletion of Septin4 prevented cardiomyocyte death and protected mice from heart failure following cardiac pressure overload. Future research will focus on regulation of calcium handling in Septin4-/- mice to determine the exact mechanisms through which Septin4 plays a detrimental role in cardiac remodeling.