Practical synthesis and biological activities of 4-hydroxy-3-methoxy-2-propene derivatives are described. The novel chalcone derivatives were prepared by acid catalysed one-step condensation of 1,3- or 1,4-diacetylbenzene and 1,3,5-triacetylbenzene with 4-hydroxy-3-methoxybenzaldehyde. They were then evaluated for free radical scavenging activity, suppression of lipopolysaccharides (LPS)-induced NO generation, and anti-excitotoxicity in vitro. It was found that all compounds showed good effects for 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, LPS-induced NO generation, and anti-neurotoxicity. Compounds 6 and 7 were potent suppressor of NO generation with the concentration range 10 µM and especially compound 8 showed very potent anti-inflammatory activity with 1 µM. In addition, the di- and tri-acetylbenzyl derivatives 6, 7, and 8 showed enhanced anti-neurotoxicity activity in cultured cortical neurons. Molecular modelling studies to investigate the chemical structural characteristics required for the enhanced biological activities interestingly revealed that compound 8 has the smallest highest occupied molecular orbital-lowest energy unoccupied molecular orbital (HOMO-LUMO) gap, which signifies easy electron and radical transfer between HOMO and LUMO in model studies.