Objective  To investigate the effect of up-regulating tumor necrosis factor alpha induced protein 3 (TNFAIP3) expression on hippocampal neurons in mice with cerebral ischemia-reperfusion.    Methods  The mice were randomly divided into 6 groups: sham group, sham empty vector group (sham-), sham TNFAIP3 high expression group (sham+), model group, model empty vector group (model- ), model TNFAIP3 high expression group (model+ ). A mouse model of middle cerebral artery occlusion and cerebral ischemia-reperfusion was established using the suture method. After the successful establishment of the model, lentivirus was injected into the hippocampus 24 hours later. Two weeks later, samples were collected and Western blotting was used to detect the expressions of TNFAIP3 and ERK signaling pathway proteins. The changes in ischemic area were observed by 2,3,5-triphenyltetrazolium chloride (TTC) staining; HE staining was used to observe the morphological changes of hippocampal neurons, and ELISA was used to detect the expressions of lipoprotein-associated phospholipase A2 (Lp-PLA2) and interleukin (IL)-8.     Results  The results of Western blotting indicated that the TNFAIP3 expression in the model group decreased significantly compared with the sham group (P<0.05); Compared with the model group, there was no significant change in TNFAIP3 expression in the model-  group (P>0.05); The TNFAIP3 expression in the model+  group increased significantly compared with the model group and model-  group(P<0.05). Compared with the sham group, the results of the sham+  group showed that the ischemic area had no significant changes in TTC staining, and there were no significant changes in hippocampal neuronal morphology, and the expressions ERK signaling pathway proteins, Lp-PLA2 and IL-8 (P>0.05); Compared with the sham-  and sham+  groups, the model group showed an increase in ischemic area, significant damage to hippocampal neurons, a decrease in the number of Nissl bodies, and a significant increase in the expressions of ERK signaling pathway proteins, Lp-PLA2, and IL-8 (P<0.05); Compared to the model-  group, the model+  group showed a decrease in ischemic area, an increase in the number of neurons in the hippocampus and the number of Nissl bodies, and a significant decrease in the expressions of ERK signaling pathway proteins, Lp-PLA2, and I-8 (P<0.05).   Conclusion  Up-regulation of TNFAIP3 may be one of the methods for repairing hippocampal neuronal damage caused by cerebral ischemia reperfusion.