Objective To compare the advantages and disadvantages of two high-glucose-induced hippocampal neuron models, and explore their application in different situations. Methods Primary hippocampal neurons and HT-22 hippocampal neuron cell lines were cultured in vitro and divided into control and high glucose groups. Neurons were purified and cell viability was measured. The effect of transfection reagents on cell viability and transfection efficiency was determined and flow cytometry was used to observe cell apoptosis. Western blot was used to detect apoptotic protein expression. Results The purity of primary hippocampal neurons was > 85%. Two high-glucose-induced neuronal cell models were successfully modeled. The high-glucose action time was 48 hours, the activity of primary neurons was stable at 80%, and the activity of HT-22 cells was >95%. The liposome transfection reagents caused damage in the two cell models. LipoRNAiMax was less toxic to HT-22 cells, which also had a high transfection efficiency. The two models showed significant apoptosis, compared with the primary neuron control group, the apoptosis rate of the primary neuron high glucose group increased, compared with the HT-22 control group, the HT-22 high glucose group increased cell apoptosis ( P< 0. 05). Compared with HT-22 high glucose group, the apoptotic rate of primary neurons high glucose group was higher, the expression of apoptotic protein Bcl-2 was decreased, and the expression of Bax was increased in primary neurons ( P< 0. 05). Compared with HT-22 control group, there was no difference in the expression of Bax in HT-22 high glucose group . Conclusions The two high-glucose-induced hippocampal neuron cell models had different advantages and disadvantages. The choice of cell model should be considered based on actual conditions.