Objective To observe the protective effect of Kangxianzengzhi granules on hippocampal neurons of juvenile epileptic rats and explore its regulating effect on Toll-like receptor 4 (TLR4) / high mobility positive group box 1 (HMGB1) / phosphorylated nuclear factor inhibitory protein α (p-IκB-α) signaling pathways. Methods Epilepsy models were established. In the positive group, 5. 9 mg / kg topiramate was dissolved in 2 mL/ 100 g normal saline, and in the low-, medium-, and high-concentration groups, 1. 28, 2. 56, and 5. 12 g / kg Kangxianzengzhi granules were infused into the stomach, respectively. Model and normal groups had normal saline infused into the stomach once a day for 4 weeks. The changes in behavior and learning / memory abilities before and after the interventions were evaluated by the Racine grading standard and Morris water maze. Hematoxylin-eosin staining was used to observe pathological changes of the hippocampus. Expression of TLR4 and HMGB1 mRNAs in the hippocampus as detected by Real-time quantitative reverse transcription polymerase chain reaction, and relative expression of TLR4, HMGB1, IκB-α, and P-IκB-α was detected by Western blot. Results After the interventions, the behavioral Racine grade and learning / memory ability indexes of the positive group and three concentration groups were improved significantly compared with those before treatments. After interventions, pathological changes of hippocampal neurons in the model group were serious, which were improved in the positive group and three concentration groups. Damage of hippocampal neurons in the positive group and three concentration groups was alleviated. The relative expression of TLR4 and HMGB1 mRNAs and proteins and the level of P-IκB-α in the model group were significantly higher than those in the normal group ( P < 0. 01 ), and those in the positive group and three concentration groups were significantly lower than those in the model group (P < 0. 01). There was no significant difference between the two groups ( P > 0. 05), and the effect of Kangxianzengzhi granules was dependent on concentration. Conclusions Kangxianzengzhi granules improve the behavioral and learning / memory abilities of young epileptic rats and the degeneration and necrosis of hippocampal neurons. The effects of high concentration drugs is better than those of topiramate. These effects are presumed to be achieved by regulating TLR4 / HMGB1 / p-IκB-α.