A series of 3-styrylchromone derivatives was synthesized and evaluated for monoamine oxidase (MAO) A and B inhibitory activities. Most of all derivatives inhibited MAO-B selectively, except compound 21. Compound 19, which had a methoxy group at R<sup>2</sup> on the chromone ring and chlorine at R<sup>4</sup> on phenyl ring, potently inhibited MAO-B, with an IC<sub>50</sub> value of 2.2 nM. Compound 1 showed the highest MAO-B selectivity, with a selectivity index of >3700. Further analysis of these compounds indicated that compounds 1 and 19 were reversible and mixed-type MAO-B inhibitors, suggesting that their mode of action may be through tight-binding inhibition to MAO-B. Quantitative structure-activity relationship (QSAR) analyses of the 3-styrylchromone derivatives were conducted using their pIC<sub>50</sub> values, through Molecular Operating Environment (MOE) and Dragon. There were 1796 descriptors of MAO-B inhibitory activity, which showed significant correlations (P < 0.05). Further investigation of the 3-styrylchromone structures as useful scaffolds was performed through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The MAO-B inhibitory activity model constructed using pIC<sub>50</sub> value index exhibited a determination coefficients (R<sup>2</sup>) of 0.972 and a Leave-One-Out cross-validated determination coefficients (Q<sup>2</sup>) of 0.914. These data suggest that the 3-styrylchromone derivatives assessed herein may be suitable for the design and development of novel MAO inhibitors.