Astrocytes play a key role in regulating aspects of inflammation and in the homeostatic maintenance of the central nervous system (CNS). However, the role of astrocytes in viral encephalitis mediated inflammation is not well documented. As Japanese encephalitis virus (JEV) infection is localized to neurons and considering the importance of astrocytes in supporting neuronal survival and function, we have exploited an experimental model of Japanese encephalitis (JE) to better understand the role of astrocytes in JE. Suckling mice pups were inoculated with the virus and 2 and 4 days later we analyzed a panel of molecules characteristic of reactive astrogliosis. We show that JEV infection increases the expression of astrocyte-specific glial fibrillary acidic protein (GFAP), the glutamate aspartate transporter (GLAST), glutamate transporter-1 (GLT-1) and ceruloplasmin (CP). The transcript levels of growth factors produced predominantly by activated astrocytes such as nerve growth factor (NGF) and ciliary neurotrophin factor (CNTF) were elevated following JEV infection. The transcript level of brain-derived neurotrophic factor (BDNF) was also elevated following JEV infection. Both NGF and CNTF were capable of preventing ROS mediated neuronal death following in vitro JEV infection to a certain extent. Taken altogether, these data indicate that increased astrogliosis following JEV infection is accompanied by the enhanced ability of astrocytes to detoxify glutamate, inactivate free radical and produce neurotrophic factors that are involved in neuronal protection. However, this elevated physiological state of astrocyte is insufficient in conferring neuroprotection, as infected animals eventually succumb to infection. The response of astrocytes to JE can be amplified to modulate the adaptive response of brain to induce neuroprotection.