Neuroinflammation can be induced under several conditions including pathogen infection such as virus. As the main immune cells in brain, microglia activation plays a pivotal role in neuroinflammation by responding to the invading pathogens (viral DNA/RNA) through toll-like receptors. Chronic activation of microglia caused by sustained viral infection will lead to persistent release of pro-inflammatory molecules, which is different from their beneficial functions under physiological conditions. Sustained exposure of neurons to the inflammatory condition can result in neuronal dysfunction as well as cell degeneration that contribute to the pathogenesis of several neurological disorders. This review proposed that during sustained infection, viral DNA/RNA activated microglia through TLRs, inducing persistent inflammatory response that causes long term, mild but irreversible changes, which ultimately contribute to the neuronal dysfunction or cell degeneration.