Curcumenol, a sesquiterpene isolated from Curcuma zedoaria is known to possess a variety of health and medicinal values which includes neuroprotection, anti-inflammatory, anti-tumor and hepatoprotective activities. The current study aim is to investigate the modulatory effects of curcumenol towards the lipopolysaccharides (LPS)-induced inflammation in BV-2 microglia. Curcumenol markedly decreased LPS-induced production of nitric oxide (NO), pro-inflammatory cytokines [(IL-6) and (TNF-α)] and pro-inflammatory proteins expression, iNOS and COX-2. Moreover, curcumenol inhibited NF-κB activation by suppressing the nuclear translocation of the NF-κB p65 subunit and blocking IκBα phosphorylation and degradation. Furthermore, an NF-κB inhibitor, ethyl 3,4-dihydroxycinnamate also known as caffeic acid ethyl ester (CAEE), attenuated LPS-stimulated iNOS and COX-2 expression, suggesting that NF-κB inhibition is a regulator in the expression of iNOS and COX-2 proteins. Further mechanistic study with an Akt inhibitor, triciribine hydrate (API-2), revealed that curcumenol acted through Akt-dependent NF-κB activation. Moreover, curcumenol inhibition on LPS-induced phosphorylation of p38 MAPK is confirmed by its inhibitor (SB 202190). These results indicate that curcumenol diminishes the proinflammatory mediators and the expression of the regulatory genes in LPS-stimulated BV-2 by inhibiting Akt-dependent NF-κB activation and downregulation of Akt and p38 MAPKs signaling.