Sepsis-associated encephalopathy (SAE) is a neurological dysfunction induced by sepsis, which is associated with high morbidity and mortality. However, at present, the cellular and molecular mechanisms of SAE have remained elusive. The pathogenesis of SAE is complex and multifactorial, in which activated inflammation is recognized as a major factor. Pathological characteristics of SAE include blood- brain barrier (BBB) disruption, reduction of cerebral blood fluid (CBF) and glucose uptake, inflammatory response and activation of microglia and astrocytes. The BBB disruption induces the leakage of immune cells and inflammatory mediators, which trigger an inflammatory response in the brain. Inflammatory mediators released by activated microglia and astrocytes cause neuronal loss and brain function defect. In the review we describe the most recent findings in the pathogenesis of SAE and focus on summarizing the major mechanisms related to SAE pathogenesis.