Sepsis-associated encephalopathy is a common brain diseases, presenting severe diffuse brain dysfunction. The umbilical cord mesenchymal stem cells have been reported to have protective role for treating diseases, while its role in sepsis-associated encephalopathy remained elusive. This brief report investigated the therapeutic effect of umbilical cord mesenchymal stem cells on sepsis-associated encephalopathy in mice model and uncovering the underlying mechanism. The sepsis-associated encephalopathy mice were injected with 3 mg/kg lipopolysaccharide. An enzyme-linked immunosorbent assay was carried out to determine the production of inflammatory cytokines. Morris water maze test was used to evaluate mice’s neurological dysfunction. Cell apoptosis and tissue injury of the cerebral cortex were assessed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and HE staining. Evans Blue leakage detection was used to examine the blood-brain barrier integrity. The protein levels were determined using Western blot. Results showed that the productions of inflammatory cytokines including interleukin 6 (IL-6), interleukin-1\beta (IL-1\beta), tumor necrosis factor \alpha (TNF-\alpha), and high mobility group box protein 1 (HMGB1) and activated NF-\kappaB were increased in sepsis-associated encephalopathy mice, which were decreased by umbilical cord mesenchymal stem cells treatment. Besides, umbilical cord mesenchymal stem cells inhibited lipopolysaccharide-induced cell apoptosis and neuron injury of the cerebral cortex in sepsis-associated encephalopathy mice. Moreover, cognitive dysfunction was observed in sepsis-associated encephalopathy mice, which was alleviated by umbilical cord mesenchymal stem cells. Furthermore, umbilical cord mesenchymal stem cells activated PI3K/AKT signaling pathway. In conclusion, umbilical cord mesenchymal stem cells alleviated inflammation, cell apoptosis and neuron injury of the cerebral cortex, and cognitive dysfunction in sepsis-associated encephalopathy animal model in a PI3K/AKT dependent pathway, making them to be a promising therapeutic strategy for treating sepsis-associated encephalopathy.