Epilepsy is a group of chronic brain disorders characterized by recurrent, abnormal neuronal firing that causes temporary CNS dysfunction. Hippocampal sclerosis (HS) is identified as the predominant pathological alteration in epilepsy, particularly in temporal lobe epilepsy. This study investigates the metabolic profiles of epileptic hippocampal tissues using proteomics and lipidomics techniques. An epilepsy model was established in SD rats via intraperitoneal injection of PTZ, with hippocampal tissue samples subsequently extracted for histopathological examination. Proteomics analysis was conducted using iTRAQ combined with LC-MS/MS, while lipidomics analysis employed UHPLC Q-TOF/MS. Proteomic analysis revealed 144 differentially expressed proteins in acute epileptic hippocampus and 83 in chronic epileptic hippocampus. Key proteins, including Nefh, Vim, Gsn, Sirt2, Cnp, Mef2d, and Ctsd, were pivotal in epileptic hippocampal tissue injury and validated through PRM. Concurrently, lipid metabolomics revealed 83 differentially expressed metabolites in acute epileptic hippocampus and 142 in chronic epileptic hippocampus. Bioinformatics analysis indicated that glycerophospholipid, sphingolipid, and glyceride metabolism pathways were crucial in epileptic hippocampal tissue injury. Integrated proteomics and lipidomics analysis revealed significant correlations between Gsn, Ctsd, and Nefh with four metabolic pathways. These findings provide deeper insights into the pathophysiological mechanisms of epileptic hippocampal tissue damage, potentially unveiling novel therapeutic avenues for clinicians.