Objective：To explore the effects of histidine decarboxylase inhibitors on lipopolysaccharide（LPS）-induced inflammation and cognitive impairment in rats in vivo. Methods：Forty-eight SD male rats were randomly divided into 4 groups with 12 rats in each group：control group，α-FMH group，LPS group and α-FMH+LPS group. Catheters were placed in the right lateral ventricle of rats with a stereotactic instrument，and a week after recovery，they were placed in an escape fear experimental instrument to learn. Then α-FMH and the same volume of normal saline were directionally injected into the lateral ventricle of rats. Half an hour after administration，LPS（1 mg/kg）was injected intraperitoneally. A day later，the ability of rats to escape fear was evaluated by behavioral experiments. The activation of microglia in the hippocampus was detected by immunohistochemistry. The expression of interleukin 6 and tumor necrosis factor α was detected by ELISA method. Results：After intraperitoneal injection of LPS，the expression of histamine in hippocampus began to increase significantly at 6 h，and was higher than the basic level within 24 h. Compared with the control group，the activation of microglia and the expression of inflammatory factors mentioned above in the hippocampus of the LPS group were increased（P < 0.01），and the freezing time of the LPS group was significantly decreased（P < 0.01）. Compared with LPS group，the activation of microglia and the expression of the inflammatory factors in the hippocampus of α-FMH+LPS group were significantly decreased（P < 0.01），and the freezing time of α-FMH+LPS group was significantly increased（P < 0.01）. Conclusion：Histidine decarboxylase inhibitor α-FMH can alleviate LPS-induced inflammation and cognitive impairment in rats by inhibiting the activation of microglia.