The microglial activation plays an important role in the progression of neurodegenerative diseases by secreting various proinflammatory cytokines and neurotoxic factors. Inhibition of microglial activation may alleviate neurodegenerative processes. To search for novel therapeutic agents against neuroinflammatory diseases, several fluorovinyloxyacetamide derivatives were screened for anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated microglial cells. From cell-based screening, it was found that a novel synthetic compound KT-15087 markedly attenuated the production of nitric oxide (NO) and tumor necrosis factor (TNF)-α in microglial cells. KT-15087 also suppressed the gene expression of inducible nitric oxide synthase (iNOS), TNF-α and interleukin (IL)-1β. The compound inhibited the nuclear translocation and DNA binding of NF-κB as well as the phosphorylation of p38 mitogen-activated protein kinases (MAPK) and c-jun N-terminal kinase (JNK). Moreover, KT-15087 showed a neuroprotective activity by reducing the cytotoxicity of LPS-stimulated microglia toward B35 neuroblastoma cells in the coculture. The neuroprotective activity of the compound was most effective when microglia were pretreated with the compound prior to LPS challenge. Taken collectively, KT-15087 has an anti-inflammatory activity in microglia, and might have a therapeutic potential for the treatment of neuroinflammatory diseases.