Novel Chalcones is considered as an important chemical for the synthesis of various physiological significance and pharmacological utilized molecules. Traditionally, chalcones are prepared by Claisen-Schmidt condensation. The structures of the newly synthesized compounds (3a-3o) were elucidated by Infrared (IR), Proton Nuclear Magnetic Resonance (1H-NMR), Mass spectroscopy. All the synthesized compounds (3a-3o) screened for their anti-fungal activity and QSAR analysis was applied to a data set of 15 obtained Novel Chalcones derivatives and the best model described a strongly correlation between the anti-fungal activity and molecular descriptors as refractivity (MR), Ovality, HOMO energy (HE), LUMO energy (LE), partition coefficient (CLogP, LogP, Connolly accessible area (CAA), Connolly molecular area (CMA), Connolly solvent excluded area (CSEV). All the parameters showed significant correlation with biological activity (r<0.8), but the molar refractivity exhibited best correlation (r>0.9) of high statistical significance >93.52%. The statistical quality of the resulting models depicted in Eqs. (1-4) is determined by r2 (r2>0.9).