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Simple Summary: Interleukin-1 converting enzyme/caspase-1 is a proinflammatory caspase that have been implicated in the pathogenesis of cardiovascular disorders, including heart failure and cardiac ischemia. In contrast, the role of the complete deletion of caspase-1 in the aging heart has not been fully studied. In this study, we aimed to understand how a lack of caspase-1 would impact the hypertrophic and apoptotic response in the mouse heart. We analyzed the hearts of ICE knockout mice to test the hypothesis that caspase-1 plays a significant role in cardiac morphology and function. Our study provides evidence that caspase-1 is an essential element in maintaining cardiac heath in aging and eliminating it will lead to hypertrophy, apoptosis, and increased vulnerability to oxidative stress. Interleukin-1β converting enzyme (ICE, caspase-1) is a thiol protease that cleaves the pro-inflammatory cytokine precursors of IL-1β and IL-18 into active forms. Given the association between caspase-1 and cardiovascular pathology, we analyzed the hearts of ICE knockout (ICE KO) mice to test the hypothesis that caspase-1 plays a significant role in cardiac morphology and function. We characterized the histological and functional changes in the hearts of ICE KO mice compared to the Wild type. The cardiomyocytes from the neonatal ICE KO mice showed an impaired response to oxidative stress. Subsequently, the hearts from the ICE KO mice were hypertrophied, with a significant increase in the left ventricular and septal wall thickness and a greater LV mass/body weight ratio. The ICE KO mice hearts exhibited irregular myofibril arrangements and disruption of the cristae in the mitochondrial structure. Proapoptotic proteins that were significantly increased in the hearts of ICE KO versus the Wild type included pErk, pJNK, p53, Fas, Bax, and caspase 3. Further, the antiapoptotic proteins Bag-1 and Bcl-2 are activated in ICE KO hearts. Functionally, there was an increase in the left ventricular epicardial diameter and volume in ICE KO. In conclusion, our findings support the important role of caspase-1 in maintaining cardiac health; specifically, a significant decrease in caspase-1 is detrimental to the cardiovascular system. [ABSTRACT FROM AUTHOR]