BACKGROUND: Diabetic cardiomyopathy (DC) is a serious complication of diabetes, characterized by myocardial fibrosis, hypertrophy, oxidative stress, and inflammation. Perillaldehyde (PAE), a natural monoterpene, has shown potential in mitigating cardiac damage. PURPOSE: This study aims to elucidate the molecular mechanism of the protective effect of PAE on the DC and the interaction between DC pathogenesis. METHODS: Network pharmacology and molecular docking were used to identify PARP1 as a core target for PAE in DC. Animal experiments involved intervening DC mice with PAE and assessing cardiac function, oxidative stress, and apoptosis. In vitro, high glucose-induced H9c2 cells were used to validate PAE's effects on cell viability and protein expression. RESULTS: The results showed that PAE improved the general condition of DC mice, reduced cardiac injury and cardiac insufficiency, decreased myocardial mitochondrial damage, and reduced apoptosis. In addition, PAE upregulated the expression of Bcl-2, downregulated Bax protein expression, inhibited Caspase-3 activity, and inhibited the expression of PARP1, TRPM2, CaN, and CaMKII proteins in DC mice and high glucose-induced H9c2 cells. CONCLUSION: Mechanically, this study clarified that PAE's inhibition of the PARP1-TRPM2-CaMKII/CaN pathway reduces calcium-activated mitochondrial damage, apoptosis, and oxidative stress in diabetic cardiomyopathy. This discovery provides an innovative therapeutic strategy for DC and an experimental foundation for PAE's drug development, with significant practical implications.