Objective To explore the protective effect and mechanism of glycyrrhizic acid on hippocampal neuron injury in epileptic rat models. Methods The epileptic rat models were established by lithium and pilocarpine kindling. The successful models were randomly divided into epilepsy group and glycyrrhizic acid group. In addition, the rats without any treatment were used as the normal control group, with 12 rats in each group. Hippocampal neuron injury and apoptosis were detected by Nissl and TUNEL staining. Mitochondrial membrane potential in the hippocampal neurons of rats was detected by JC?1 method. The activity of aspartic acid protein hydrolase 3 (caspase 3) and caspase 9 was detected by colorimetric assay. The expressions of cleaved?caspase 3, 9, B lymphocyte tumor?2 (Bcl?2), Bcl?2 related X protein (Bax), cytochrome C (CytC) and apoptotic protease?activating factor (Apaf?1) protein in the hippocampal tissues of rats were detected by western blot assay. Results Compared with the normal group, the number of neurons was reduced ( P <0.01), the number of TUNEL?positive cells was increased ( P < 0.01), mitochondrial membrane potential was decreased ( P < 0.01), caspase 3 and 9 activity was increased ( P < 0.01), the expressions of Bcl?2 and mitochondrial CytC were down?regulated ( P < 0.01), the expressions of Bax, cytoplasm CytC and Apaf?1 were up?regulated ( P < 0.01) in the epilepsy group. Compared with the epilepsy group, the number of neurons was increased ( P < 0.01), the number of TUNEL?positive cells was reduced ( P < 0.01), mitochondrial membrane potential was increased ( P < 0.01), caspase 3and 9 activity was decreased ( P < 0.01), the expressions of Bcl?2 and mitochondrial CytC were up?regulated ( P <0.01), the expressions of Bax, cytoplasm CytC and Apaf?1 were down?regulated ( P < 0.01) in the glycyrrhizic acid group. Conclusions These results suggest that glycyrrhizic acid can inhibit the hippocampal neuron injury in epileptic rats by blocking the mitochondrial pathway.