Background: Epigenetic histone acetylation is a major event controlling cell functions, such as metabolism, differentiation and repair. Here, we aim to determine whether Valproic acid (VPA), a FDA approved inhibitor of histone deacetylation for bipolar disease, could protect heart against myocardial infarction (MI) injury and elucidate key molecular pathways. Methods: VPA was administrated to MI rats at different time points, onset and after MI injury. Echocardiography, histology, serum biology assays, and gene expression, inhibition, and over-expression were performed to characterize the systolic function, infarct size, gene and signaling pathways. Findings: VPA treatment reduced the infarct size by ~50% and preserved the systolic function of heart after acute MI in rats. Even 60 min after infarction, VPA treatment significantly decreased infarct size. Furthermore, long-term treatment of VPA markedly improved myocardial performance. VPA regulated gene expression essential for cell survival and anti-inflammatory response. Consequently, oxidative stress and cell death were notably reduced after VPA treatment. Moreover, Foxm1 was identified as a potential key target of VPA. Overexpression of Foxm1 provided similar heart protective effect to VPA treatment. Particularly, both VPA treatment and Foxm1 over-expression repressed inflammatory response after MI for heart protection. In contrast, inhibition of Foxm1 activity abolished the cardiac protective effect of VPA. VPA mediated CM protection through Foxm1 upregulation was also identified in a human ESC derived CM hypoxia/reperfusion system. Interpretation: VPA treatments significantly reduce cardiac damage after MI and the cardioprotective effect of VPA is likely mediated via Foxm1 pathway. Fund: This work was mainly supported by 1R01HL109054.