Background: Epilepsy is a disease caused by paroxysmal abnormal supersynchronous electrical activity of brain neurons, and it is also one of the most common illnesses in neurology. Among the causes, hippocampal sclerosis may be one of the main causes of temporal lobe epilepsy. However, the pathogenesis of hippocampal sclerosis in epilepsy remains unclear. Methods: We established an epilepsy model by intraperitoneal injection of pentetrazol (PTZ) into Sprague-Dawley rats, and applied isobaric tags for relative and absolute quantitation (iTRAQ) technology to identify differentially expressed proteins (DEPs) in the hippocampus. We quantified a total of 3782 proteins. DEPs were defined as proteins with a fold change >1.2 (or 0.83) and a Q value (p-adjusted) 0.05. Results: Comparing the epilepsy group and the control group, we identified 170 DEPs, comprising 109 upregulated and 61 downregulated proteins. According to bioinformatics analysis, the DEPs were primarily involved in long-term potentiation, the calcium signalling pathway, aldosterone synthesis and secretion, carbon metabolism, and dopaminergic synapses. Four of these proteins were validated using parallel reaction monitoring (PRM), including Glud1, Atp1a2, Prkcg and Arpc3. Conclusions: Our research results may provide further insight into the molecular pathology of hippocampal injury in epilepsy.