Our preliminary study found that the long noncoding RNA (LncRNA)-5657 can reduce the expression of inflammatory factors during inflammatory reactions in rat glial cells. However, the role played by LncRNA-5657 during septic brain injury remains unclear. In the present study, rat models of septic encephalopathy were established by cecal ligation and puncture, and then the rats were treated with a hippocampal injection small hairpin RNA (shRNA) against LncRNA-5657 (sh-LnCRNA-5657). The sh-LncRNA-5657 treatment reduced the level of neuronal degeneration and necrosis in the rat hippocampus, reduced the immunoreactivities of aquaporin 4, heparanase, and metallopeptidase-9, and lowered the level of tumor necrosis factor-alpha. Glial cells were pre-treated with sh-LncRNA-5657 and then treated with 1 µg/mL lipopolysaccharide. Sh-LncRNA-5657 transfection decreased the expression of LncRNA-5657 in lipopolysaccharide-treated glial cells and decreased the mRNA and protein levels of tumor necrosis factor-alpha, interleukin-1β, and interleukin-6. These findings suggested that LncRNA-5657 expression can significantly reduce the inflammatory reaction during septic encephalopathy and induce protective effects against this disease. This study was approved by the Institutional Ethics Committee at the First Affiliated Hospital of Nanchang University of China (approval No. 2017-004) in 2017.