Abstract: Objective To observe the effect of dexpramipexole on cognitive function in mice with sepsis-associated encephalopathy (SAE). Methods A total of 120 adult male C57BL/6 mice were randomly divided into four groups: a sham surgery + normal saline group (group SS, n=20), a sham surgery + dexpramipexole group (group SD, n=20), a cecal ligation and puncture + normal saline group (group CS, n=40), and a cecal ligation and puncture + dexpramipexole group (group CD, n=40). According to the grouping, mice were intraperitoneally injected with dexpramipexole at 5 mg/kg or an equal volume of normal saline 1 h before surgery and on post-surgery six consecutive days. On post-operation day 7, mitochondrial changes in the hippocampus, reactive oxygen species (ROS), and dynamin-related protein 1 (DRP1) protein content were measured. On post-surgery day 14, survived mice underwent the open field test and conditioned fear experiment. The total exploration distance,residence time in the central mesh, and rigidity time were measured. Results Compared with the SS group, the CS group exhibited significantly shortened freezing time in the freezing time of context test, increases in the number of abnormal mitochondria in the hippocampus, and increased ROS levels and DRP1 content. Compared with group CS, group CD showed significantly extended freezing time in the freezing time of context test, decreases in the number of abnormal mitochondria in the hippocampus, and reduced ROS levels and DRP1 content. Conclusions Dexpramipexole alleviates cognitive dysfunction in SAE mice, possibly through inhibiting the elevation of hippocampal DRP1 and protecting mitochondrial function.