Chlorpromazine and clozapine are antipsychotic agents used to relieve symptoms of early-diagnosed schizophrenia. In this study, we used proteomics technology to screen the protein aberration in Sprague-Dawley rats treated with these two antipsychotic agents. Our goal was to identify the effects of antipsychotics on hippocampal proteins in rats. Protein expression profiles were compared in each experimental group using two-dimensional gel electrophoresis and identified using matrix-assisted laser desorption/ionisation time of flight mass spectrometry. Malate dehydrogenase, peroxiredoxin 3, vacuolar ATP synthase subunit beta and mitogen-activated protein kinase kinase 1 were found to have altered expression levels in the groups treated with antipsychotics compared with the matched controls. These findings should contribute to identifying new targets for disease preventing pharmacological agents and be beneficial for the development of more effective agents.