Nimbolide, a limonoid compound found in the neem plant, was investigated for effects on neuroinflammation in BV-2 microglia activated with lipopolysaccharide (LPS). Cultured BV-2 cells were treated with nimbolide (125, 250 and 500 nM) followed by stimulation with LPS (100 ng/ml). Results showed that nimbolide caused a significant reduction in the levels of TNFα, IL-6, IFNγ, NO/iNOS and PGE 2/COX-2 in LPS-activated BV-2 cells. Further experiments revealed that LPS-induced increased expression of phospho-p65 and phospho-IκBα proteins were reduced in the presence of nimbolide. Also, LPS-induced NF-κB acetylation, increased binding to consensus sites and transactivation, as well as phosphorylation of p38 and JNK MAPKs were reduced by nimbolide. Reduction of cellular ROS generation by nimbolide was accompanied by a reduction in gp91phox protein levels, while antioxidant effects were also observed through elevation in protein levels of HO-1 and NQO-1. It was observed that treatment of BV-2 microglia with nimbolide resulted in reduced levels of cytoplasmic Nrf2, which was accompanied by increased levels in the nucleus. Furthermore, treatment with this compound resulted in increased binding of Nrf2 to antioxidant responsive element (ARE) consensus sites accompanied by enhanced ARE luciferase activity. Knockdown experiments revealed a loss of anti-inflammatory activity by nimbolide in cells transfected with Nrf2 siRNA. Treatment with nimbolide resulted in nuclear accumulation of SIRT-1, while siRNA knockdown of SIRT-1 resulted in the reversal of anti-inflammatory activity of nimbolide. It is proposed that nimbolide reduces neuroinflammation in BV-2 microglia through mechanisms resulting in dual inhibition of NF-κB and MAPK pathways. It is also proposed that activation of Nrf2 antioxidant mechanisms may be contributing to its anti-inflammatory activity.