Objective To explore the improvement and mechanism of Glatiramer acetate (GA) on perioperative neurocognitive disorders (PND) in mice. Methods Fifty-four aged male C57BL/6J mice were divided into 3 groups(n=18 each) using a random number table method: control group（C group）, operation group(S group), drug group(GA group). S and GA group mice were underwent abdominal surgery. Mice in the GA group received four subcutaneous injections of GA 200ug/d from 1d before to 2d after surgery. Each group of 6 mice were subjected to a 5-day Morris water maze training, the escape latency and the frequency of crossing the platform were recorded 3 days after the operation. Venous blood was drawn from each remaining group of mice after 3d postoperative execution, the serum inflammatory factors IL-1β and IL-6 levels were measured by ELISA. 6 mice in each group were selected and sacrificed, and the hippocampus tissue was collected to detect the activation state of microglia by immunohistochemistry. The gene expression level of CCL2 was detected by real-time quantitative PCR in the remaining mice. Results Compared with C group, the S group had prolonged escape latency and reduced cross-platforming, there was no significant change in group GA (P0.05); Compared with the S group, the GA group had a shorter escape latency, an increased number of cross-platforms(P0.05). Compared with group C, peripheral blood IL-1β and IL-6 were higher in group S(P0.05); Compared with group S, IL-1β and IL-6 were significantly lower in group GA(P0.05). Compared with C group, the number of activated microglia in the hippocampus of S group was significantly increased (P0.05), but the GA group was not(P0.05); Compared with the S group, the activated microglia in the GA group were significantly reduced (P0.05). And compared with the C group, the CCL2 expression on the choroid plexus of the mice in the S group was increased (P0.05), but the expression in the GA group was not statistically significant (P0.05); Compared with the S group, the GA group had a lower CCL2 expression on the choroid plexus (P0.05). Conclusion Glatiramer acetate could improve the cognitive deficits in perioperative neurocognitive disorders in mice after abdominal surgery. The potential mechanism could be reducing the systemic inflammatory response, inhibiting choroid plexus CCL2 expression, and reducing microglia activation, thereby reducing the neuroinflammatory response.