Microglia-mediated neuroinflammation is an important contributor to the pathogenesis of neurodegenerative diseases. Inhibition of neuroinflammation has been proved to be effective in neurodegenerative diseases treatment. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key mediator of endogenous inducible defense systems in the body. In response to oxidative stress, Nrf2 translocates to the nucleus and binds to specific DNA sites termed as anti-oxidant response elements to initiate transcription of cytoprotective genes, such as hemeoxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate: quinine oxidoreductase-1 (NQO1). However, insufficient Nrf2 activation has been closely associated with the progress of neurodegenerative diseases. New findings have linked activation of Nrf2 signaling to anti-inflammatory effects. Icariin (ICA), a natural compound derived from Herba Epimedii, possesses amounts of pharmacological activities, such as anti-aging, anti-oxidation and anti-inflammatory effects. Recent studies have confirmed that ICA exerted neuroprotection against neurodegenerative diseases. However, the mechanisms underlying ICA-mediated neuroprotection were not fully understood. In the present study, microglia BV-2 cell lines were performed to investigate the anti-neuroinflammatory effects of ICA and the mechanisms of actions. Results showed that ICA suppressed lipopolysaccharide (LPS)-induced microglial pro-inflammatory factors production. In addition, activation of Nrf2 signaling pathway participated in ICA-mediated anti-neuroinflammation, as evidenced by the following observations. First, Nrf2 siRNA reversed ICA-reduced microglial activation and pro-inflammatory factors release. Second, a selective inhibitor of HO-1 abolished ICA-mediated anti-neuroinflammatory actions. This study will give us an insight into the potential of Nrf2 and neuroinflammation in terms of opening up an alternative therapeutic strategy for neurodegenerative diseases.