A new microwave method (MM) has been developed for the synthesis of a series of 16 substituted ferrocenyl chalcones using acetylferrocene () with different aldehydes () and comparing it with conventional method (CM). The synthesized compounds were characterized by various spectroscopic techniques IR, HR-MS, H NMR, and C NMR. The time required for completion of reaction in MM varied from 1 to 5 min as compared to CM which required 10-40 h. All the synthesized compounds were screened for antifungal activity against and . fungicidal activity revealed that compound (ED = 23.24 mg L) was found to be most active against . But in case of , compound (ED = 29.9 mg L) showed highest activity. The nematicidal activity revealed that the compound was more potent with LC values of 10.67, 7.30, and 4.55 ppm at 24, 48, and 72 h, respectively. 2D-Quantitative Structural Activity Relationship (2D-QSAR) analysis of these ferrocenyl chalcones was carried out by developing three different models namely Partial Least Squares (PLS, Model 1), Multiple Linear Regression (MLR, Model 2) and Principal Component Regression (PCR, Model 3). Statistical significance and predictive ability of these models were assessed by internal and external validation and also verified by leave one-out cross-validation. QSAR study revealed that MLR for ( = 0.999, = 0.996), PLS for ( = 0.934, = 0.749) and PCR for ( = 0.878, = 0.772) were the best model. The physico-chemical parameters were calculated using VLife MDS 4.6 software. QSAR study could be employed for structure optimization to achieve better activity.