Today, environmental pollution has been found to be one of the causes of various diseases, including brain and nervous system diseases. In particular, neurodegenerative diseases have been found to be caused by hyperactivation of immune system cells such as microglia. Preventive and therapeutic measures are needed to suppress them. Hirudo is known as a traditional herbal medicine, based on its multiple biological activities such as anti-eczema and anti-coagulation. In the present study, the anti-neuroinflammatory potential of hirudo extract was investigated in lipopolysccharide (LPS)-stimulated BV2 microglial cells and in mice. Hirudo extract significantly inhibited LPS-stimulated nitric oxide (NO) production and cytokine (IL-1Ra, KC, MCP-5, and RANTES) expression in a dose-dependent manner without causing cytotoxicity. Pretreatment with hirudo extract suppressed LPS-induced NF-κB p65 nuclear translocation. Moreover, hirudo extract reduced LPS-stimulated microglial acitivation and improved memory impairments. The results demonstrated that hirudo extract exerts anti-neuroinflammation activities, partly through inhibition of the NF-κB signaling pathway. These findings suggest that hirudo extract might have therapeutic potential with respect to neuroinflammation and neurodegenerative diseases.