Neuroinflammation is among the common pathophysiological process involved in neurodegenerative diseases' onset and progression. Several pharmacologically active compounds have been revealed to possess anti-neuroinflammatory and neuroprotection activities and thus attenuate disease progression. This research was designed to evaluate the neuroprotection activity of two distinct potential compounds, fagaramide and arvanil, on LPS- stimulated BV2 microglia and H2O2- induced SH-SY5Y neurotoxicity. BV2 microglia were treated with arvanil (0.1, 0.25 and 0.5 μM) or fagaramide (5, 10 and 20 μM) and then stimulated with LPS (100 ng/ml). The results revealed that both arvanil and fagaramide could significantly reduce the levels of the pro-inflammatory cytokines (TNF-α and IL-6). In addition, the protein expression of iNOS and COX-2 with their related mediators, NO and PGE2, respectively, were attenuated significantly when LPS-activated BV2 cells and pre-treated with arvanil and fagaramide. For further investigation on the molecular mechanisms behind the anti-neuroinflammatory activities of arvanil and fagaramide, their modulated effects on the inflammatory signalling pathways have been examined. The results demonstrated that both compounds exerted their anti-neuroinflammatory effects independent of NF-B, MAPKs and Akt signalling pathways in LPS-activated BV2 microglia. Furthermore, the activities of arvanil and fagaramide were not mediated by the activation of the Nrf2/HO-1/NQO1 antioxidant axis in BV2 microglia. The anti-neuroinflammatory activity of arvanil in LPS-stimulated microglia was not possibly mediated through binding to CB1, CB2 and TRPV1 receptors. Furthermore, results from the activity of arvanil and fagaramide on H2O2-induced apoptosis suggested that both compounds could not attenuate the neurotoxicity in differentiated SH-SY5Y neuroblastoma cells, which was induced by H2O2. Collectively, arvanil and fagaramide inhibited neuroinflammation independently from the modulation of NF-B, MAPKs and Akt signalling pathways. The anti-neuroinflammatory activities of arvanil and fagaramide were not mediated by the upregulation of the Nrf2 pathway. Arvanil and fagaramide did not protect the SH-SY5Y neuroblastoma cells from the neurotoxicity of H2O2, suggesting that arvanil and fagaramide activities might be achieved by inhibiting neuroinflammation without reversing neurotoxicity.