Objective: To explore the effects of meningeal lymphatic vessel transport dysfunction on lipopolysaccharide (LPS)-induced central nervous system inflammation in mice. Methods: Firstly, sixteen C57BL/6 mice were randomly divided into 4 groups, normal saline was injected intraperitoneally in the Control group. The LPS groups were injected intraperitoneally with LPS(2 mg/kg) , the transport function of meningeal lymphatic vessels, activation of microglia and levels of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the hippocampus were observed after 12h, 24 h and 72 h. Secondly, eight mice were randomly assigned to 2 groups: Control group and VEGFR3 inhibitor MAZ51 group, to observe the effects of MAZ51 on the transport function of meningeal lymphatic vessels. Finally, twenty-four mice were divided into 4 groups as follows: Control group, MAZ51 group, LPS group, and LPS+MAZ51 group. MAZ51(10 mg/kg) was preinjected intraperitoneally into MAZ51 group and LPS + MAZ51 group for 5 days per week with a total of 30 days. After 6 weeks, LPS was injected into LPS group and LPS + MAZ51 group. A day later, behavioral experiments that assess the ability of mice to escape from fear were conducted; the activation of microglia in the hippocampus was measured by immunohistochemistry; the expression of IL-6 and IL-1β was evaluated by ELISA method. Results: The area of LYVE-1 in meninges and the area of OVA-647 in deep cervical lymph nodes were significantly decreased 24 h after intraperitoneal injection of LPS(P<0.01), and was lower than the basal level for 72 h(P<0.01).The activation of microglia and levels of IL-6 and IL-1β in the hippocampus were significantly increased after 24h(P<0.01). Compared with the Control group, the area of OVA-647 fluorescence in the MAZ51 group was significantly reduced(P<0.01). The activation of microglia and the expression of inflammatory factors in the hippocampus of mice in the LPS+MAZ51 group was increased(P<0.01) and the freezing time was significantly reduced(P<0.01). Conclusion: Impairing transport function of meningeal lymphatic vessels aggravates LPS-induced central inflammation and cognitive dysfunction in mice by increasing inflammatory mediator accumulation and activating microglia.