Abstract: Objective To explore the improvement effect and mechanism of chlorpheniramine (CLE) on cognitive dysfunction in a sepsis-associated encephalopathy (SAE) mouse model. Methods Forty 8-week-old male C57BL/6 mice were randomly divided into four groups (n=10): Control group, CLE group, Lipopolysaccharide (LPS) group, and LPS+ CLE group. The LPS + CLE group and CLE group were intraperitoneally administered with chlorpheniramine at 10 mg·kg^-1·d^-1 for 14 consecutive days, with 5 mg/kg of LPS or an equal volume of normal saline administered on day 7. The LPS group and Control group were intraperitoneally administered with equal volumes of the solvent for 14 days, with 5 mg/kg of LPS or normal saline administered on day 7. Behavioral changes were assessed using the open field test, novel object recognition test, and Y-maze test. Western blot was used to detect the levels of hippocampal interleukin-6 (IL-6), interleukin-1β (IL-1β), and myelin basic protein (MBP). Immunofluorescence was used to observe hippocampal microglial cell counts, as well as the expression of MBP, and c-fos, a marker of activity-related neurons. Results Compared with the Control group, the LPS group showed no statistical differences in the total distance traveled or time spent in the center zone of the open field test (P>0.05). However, the LPS group presented decreases in the discrimination index in the novel object recognition test, and the spontaneous alternation rate in the Y-maze test, along with increased IL-6 and IL-1β expression levels, microglial cell counts, as well as reduction in MBP expression and the number of c-fos-positive neurons (P<0.05). Compared with the LPS group, the LPS + CLE group showed no statistical differences in the open field test (P>0.05). However, the LPS + CLE group presented increases in the discrimination index in the novel object recognition test, spontaneous alternation rate in Y-maze test, along with increases in MBP expression and the number of c-fos-positive neurons (P<0.05). Conclusions Chlorpheniramine may improve cognitive dysfunction in the SAE mouse model by promoting hippocampal myelin regeneration and increasing the number of activity-related neurons.