In this paper, the synthesis of 48 chalcones and their in vitro antifungal activity against Aspergillus flavus NCIM 594, Fusarium proliferatum NCIM1105, Aspergillus niger NCIM 596 and Candida tropicalis NCIM 3556 are reported. Predominantly, the active compounds (6, 9, 14, 27, and 47) against all four fungi have found to have electron withdrawing substitutions in their para substitution in B-ring. Quantitative structure-activity relationship indicated that the antifungal activities are correlated with absorption distribution metabolism and excretion, electrophilicity, spatial and topological descriptors. The statistical measures such as r2 (0.68-0.71), r2-adj (0.62-0.66), q2 (0.60-0.61) and F-ratio (12-17) are reasonable. The data is divided into training and a test set, the former is used to develop the models, and the later is used to test their predictive capability. The predictions are found to be within the 99% confidence level except for two of the cases. SEM (scanning electron microscopy) and BacLight Live/Dead assay indicate that the chalcones act by disrupting the fungal cell wall. © 2009 John Wiley and Sons A/S.