Sepsis survivors long-term memory loss, cognitive impairment, decreased quality of life, and even death were very common in sepsis survivors after hospital discharge, which induce a huge economic and psychological burden on families and society. In recent years, the cognitive dysfunction induced by sepsis has become the focus of medical research. High Mobility Group Box 1 (HMGB1) as a key late inflammatory mediator during sepsis has involved in the pathogenesis of sepsis induced cognitive dysfunction. However, it is not yet clear about the mechanism of cognitive dysfunction mediated by HMGB1. At present, mediating inflammation and neuroinflammation, the destruction of the blood-brain barrier, the activation of oxidative stress and microglia, the inflammatory damage of hippocampus were main mechanism in the effect of HMGB1 on cognitive dysfunction during sepsis. To further explore the detail of HMGB1-mediated cognitive impairment during sepsis and its specific signaling pathway is critically encouraged to find new targets for prevention and treatment.