Abstract: Objective to investigate the effect and mechanisms of oxymatrine(OMT) on lipopolysaccharide(LPS) induced apoptosis of hippocampal neurons. Methods According to the release rate of lactate dehydrogenase(LDH) in hippocampal neurons, the concentration of OMT was selected for experimental grouping. There were seven groups:normal group, LPS group, Aspirin+LPS group, OMT group, OMT low-dose+LPS group, OMT mid-dose+LPS group and OMT high-dose+LPS group. Apoptosis rate was detected by flow cytometry. The nuclear translocation of NF-κB/P65 was observed by immunofluorescence. The level of tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in culture supernatants of hippocampal neurons were determined by Enzyme-linked immunosorbent assay(ELISA). Results The apoptosis rate of hippocampal neurons in the LPS group was higher than normal group(P<0.01), and OMT could significantly reduce LPS stimulated apoptosis rate of hippocampal neurons(P<0.05). LPS promoted NF-κB/P65 shifted from cytoplasm to the nucleus, and increased the level of TNF-α and IL-1β in the culture supernatant of hippocampal neuron, while OMT reduced the LPS on hippocampal neurons NF-κB/P65 nuclear translocation and reduce the level of TNF-α and IL-1β. Conclusion LPS could induce NF-κB/P65 nuclear translocation in hippocampal neurons and result in increased levels of inflammatory factors TNF-α and IL-1β. OMT could weaken the nuclear translocation of NF-κB/P65 induced by LPS and reduce the level of TNF-α and IL-1β, which in turn to inhibit apoptosis of hippocampal neurons.