Monilinia fructicola causes brown rot on a wide variety of stone fruits, causing several losses in the field and during storage of fruits. Due to the diverse biological activity of chalcones and their derivatives, they have emerged as a promising alternative for controlling phytopathogenic fungi. The aim of this study was to synthesize 3′,4′-methylenedioxychalcone derivatives and evaluate their in vitro inhibitory effect on mycelial growth and the conidial germination of M. fructicola. Additionally, a molecular docking study and the prediction of lipophilicity were carried out to investigate their chemical behavior. The results showed that compound F exhibited the most potent antifungal activity, with EC₅₀ and MIC values of 20.61 µg/mL and <10 µg/mL for mycelial growth and conidial germination, respectively, presenting an adequate lipophilicity (Log p values = 2.79), which would allow proper diffusion through the fungal cell membrane. The in silico study revealed a great number of interactions between compound F and the different active sites of the succinate dehydrogenase enzyme, suggesting a favorable interaction with a binding energy score value of −6.9 kcal/mol, similar to CBE, the native ligand of this enzyme. These types of compounds could provide preventive protection in various stone and other crops.