Epilepsy is a difficult-to-manage neurological disease that can result in organ damage, such as cardiac injury, that contributes to sudden unexpected death in epilepsy (SUDEP). Although recurrent seizure-induced cardiac dysregulation has been reported, the underlying molecular mechanisms are unclear. We established an epileptic model with Sprague-Dawley rats by applying isobaric tags for a relative and absolute quantification (iTRAQ)-based proteomics approach to identify differentially expressed proteins in myocardial tissue. A total of seven proteins in the acute epilepsy group and 60 proteins in the chronic epilepsy group were identified as differentially expressed. Bioinformatics analysis suggested that the pathogenesis of cardiac injury in acute and chronic epilepsy may be due to different molecular mechanisms. Three proteins, a receptor for activated protein kinase C1 (RACK1), aldehyde dehydrogenase 6 family member A1 (ALDH6A1), and glycerol uptake/transporter 1 (Hhatl), were identified as playing crucial roles in cardiac injury during epilepsy and were successfully confirmed by Western blot and immunohistochemistry analysis. Our study not only provides a deeper understanding of the pathophysiological mechanisms of myocardial damage in epilepsy, but also suggests some potential novel therapeutic targets for preventing cardiac injury and reducing the incidence of sudden death due to heart failure.