Objective To explore the effect of regulating IL-17A/IL-17R pathway on long-term cognitive function in mice with sepsis. Methods A mouse model of sepsis was established by cecal ligation and perforation (CLP)In the first part,the experimental mice was divided of 6 groups, SHAM, CLP7, CLP12, CLP9,CLP14,CLP28d, with 5 mice in each group. IL-17A, TNF-α, IL-β were determined by ELISA,Iba-1 and CD11b were detected by immunofluorescence, and the cognitive function of mice was measured by jump test and open field test. In the second part, 80 mice were divided into CLP 14 day intraventricular injection group and CLP 28 day intraventricular injection group. Then the two groups were divided into Sham group, CLP group, Sham+IL-17A group, CLP+IL-17A group, CLP+anti-IL-17A group, CLP+IsotypeA group, CLP+anti-IL-17R group and CLP+IsotypeB group, with 5 animals in each group. According to the groups, the mice were pretreated with recombinant IL-17A, anti-IL-17A antibody, anti-IL-17R antibody, corresponding homologous control antibody or normal saline, and then the changes of cognitive function, the activation level of microglia cells and the levels of pro-inflammatory cytokines were detected. The detection method was the same as that in the first part. Results The first part of the study showed that the levels of inflammatory factors (IL-17A, TNF-α, IL-1β) significantly increased in CLP7d group compared with SHAM group, and the number of central and horizontal crossing grids decreased, the memory latency was shortened, and the cognitive function was significantly impaired. The levels of inflammatory factors (IL-17A, TNF-α, IL-1β) slowly increased from 7 to 28 days, the number of central and horizontal crossing grids decreased, the memory latency was shortened, and the cognitive function continued to decline. The second part showed that compared with CLP group, the levels of inflammatory factors (TNF-α, IL-1β) in CLP14 d and 28 d groups injected with IL-17A significantly increased the number of central and horizontal crossing grids decreased, the memory latency was shortened, and the cognitive function was significantly impaired. However, the levels of inflammatory factors (TNF-α, IL-1β) in CLP14 d and 28 d groups after anti-IL-17A/17R injection significantly decreased, the number of central and horizontal crossing grids increased, the memory latency was prolonged, and the cognitive function was significantly improved, with statistically significant differences among all the groups (P<0.05). Conclusions The level of IL-17A in brain homogenate during sepsis is related to the long-term cognitive dysfunction of sepsis mice. Intervention of IL-17A/IL-17R pathway can inhibit the activation of microglia and reduce the immune inflammatory response in the brain, thereby improving the long-term cognitive dysfunction of sepsis mice.