Ginsenoside Rb1 (GRb1) is a major ingredient of ginseng and has a wide range of neuroprotection effects. Neuroinflammation is a feature of neurodegenerative conditions and is characterized by microglia activation and the expression of major inflammatory mediators. The present study investigated the modulatory effect of GRb1 on microglia activation, the expression of pro-inflammatory cytokines and cyclooxygenase (COX)-2 in the brain induced by systemic lipopolysaccharide (LPS) treatment in C57BL/6 mice. Systemic LPS treatment induces immediate microglia activation in the brain. Based on this information, GRb1 was administered orally, at doses of 10 and 20 mg/kg, 1 h prior to the LPS (3 mg/kg, intraperitoneally) injection. At a dose of 20 mg/kg GRb1 attenuated Iba1 protein expression and morphological activation of microglia by LPS. GRb1 significantly reduced the upregulation of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 mRNA in the brain tissue at 4 h after LPS injection. In addition, the expression of COX-2 mRNA and protein in the brain tissue were also attenuated at the 20 mg/kg dose of GRb1. These results indicate that GRb1 plays a modulatory role in microglia activation and neuroinflammation. This study shows that GRb1 attenuates microglia activation in the brain using an in vivo animal model. Copyright © 2012 John Wiley & Sons, Ltd.