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Arsenic trioxide (ATO) is an effective chemotherapeutic agent but causes severe cardiotoxicity, which limits its clinical application. 10-Gingerol (10Gin) is a major bioactive component of ginger, yet its cardioprotection and the mechanism underlying its effects against ATO-induced heart injury (HI) have not been fully elucidated. This study integrated network pharmacology (NP) analysis, in vivo mouse models, and in vitro cell experiments to investigate the cardioprotection of 10Gin against ATO-induced HI and its underlying mechanisms. NP analysis identified 32 overlapping therapeutic targets of 10Gin, ATO, and HI, among which the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was the most significantly enriched cardiovascular-related pathway. Our in vivo experimental results demonstrated that 10Gin treatment significantly ameliorated ATO-induced histopathological injury and cardiac dysfunction in mice. Echocardiographic evaluation showed that 10Gin improved ATO-induced systolic dysfunction, as evidenced by increased ejection fraction and fractional shortening. Specifically, 10Gin reduced serum levels of myocardial injury markers, enhanced endogenous antioxidant enzyme activities, decreased reactive oxygen species production, downregulated pro-inflammatory cytokine mRNA expression, and inhibited cardiomyocyte apoptosis. In vitro experiments involving H9c2 cells and AC16 human cardiomyocytes showed that 10Gin enhanced cell viability, attenuated apoptosis and oxidative stress, thereby exerting cardioprotective effects. Moreover, 10Gin significantly increased the p-PI3K/PI3K and p-AKT/AKT ratios both in vivo and in vitro. Notably, the in vitro cardioprotection of 10Gin could be partly reversed by the PI3K inhibitor LY294002. These findings indicate that 10Gin alleviates ATO-induced HI through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, which are likely mediated by PI3K/AKT activation, thereby supporting further investigation of 10Gin as a potential adjunctive candidate.